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1
Choi, Sung Kyung, Myoung Jun Kim, and Jueng Soo You. "SMARCB1 Acts as a Quiescent Gatekeeper for Cell Cycle and Immune Response in Human Cells." International Journal of Molecular Sciences 21, no. 11 (June 1, 2020): 3969. http://dx.doi.org/10.3390/ijms21113969.
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Switch/sucrose non-fermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin (SMARC) subfamily B member 1 (SMARCB1) is a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, one of the adenosine triphosphate (ATP)-dependent chromatin remodeler complexes. The unique role of SMARCB1 has been reported in various cellular contexts. Here, we focused on the general role of the ubiquitous expression of SMARCB1 in a normal cell state. We selected ARPE19 (human primary retinal pigment epithelium) and IMR90 (from human fetal lung fibroblasts) cell lines as they have completely different contexts. Furthermore, although these cell lines have been immortalized, they are relatively close to normal human cells. The loss of SMARCB1 in ARPE19 and IMR90 cells reduced cell cycle progression via the upregulation of P21. Transcriptome analysis followed by SMARCB1 knockdown in both cell lines revealed that SMARCB1 was not only involved in cell maintenance but also conferred immunomodulation. Of note, SMARCB1 bound to interleukin (IL) 6 promoter in a steady state and dissociated in an active immune response state, suggesting that SMARCB1 was a direct repressor of IL6, which was further confirmed via loss- and gain-of-function studies. Taken together, we demonstrated that SMARCB1 is a critical gatekeeper molecule of the cell cycle and immune response.
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Nguyen, Thinh T., Joanne G. A. Savory, Travis Brooke-Bisschop, Randy Ringuette, Tanya Foley, Bradley L. Hess, Kirk J. Mulatz, Laura Trinkle-Mulcahy, and David Lohnes. "Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity." Journal of Biological Chemistry 292, no. 8 (January 12, 2017): 3389–99. http://dx.doi.org/10.1074/jbc.m116.752774.
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The packaging of genomic DNA into nucleosomes creates a barrier to transcription that can be relieved through ATP-dependent chromatin remodeling via complexes such as the switch-sucrose non-fermentable (SWI-SNF) chromatin remodeling complex. The SWI-SNF complex remodels chromatin via conformational or positional changes of nucleosomes, thereby altering the access of transcriptional machinery to target genes. The SWI-SNF complex has limited ability to bind to sequence-specific elements, and, therefore, its recruitment to target loci is believed to require interaction with DNA-associated transcription factors. The Cdx family of homeodomain transcript ion factors (Cdx1, Cdx2, and Cdx4) are essential for a number of developmental programs in the mouse. Cdx1 and Cdx2 also regulate intestinal homeostasis throughout life. Although a number of Cdx target genes have been identified, the basis by which Cdx members impact their transcription is poorly understood. We have found that Cdx members interact with the SWI-SNF complex and make direct contact with Brg1, a catalytic member of SWI-SNF. Both Cdx2 and Brg1 co-occupy a number of Cdx target genes, and both factors are necessary for transcriptional regulation of such targets. Finally, Cdx2 and Brg1 occupancy occurs coincident with chromatin remodeling at some of these loci. Taken together, our findings suggest that Cdx transcription factors regulate target gene expression, in part, through recruitment of Brg1-associated SWI-SNF chromatin remodeling activity.
3
Liu, Hongyu, Yang Zhao, Guizhen Zhao, Yongjie Deng, Y. Eugene Chen, and Jifeng Zhang. "SWI/SNF Complex in Vascular Smooth Muscle Cells and Its Implications in Cardiovascular Pathologies." Cells 13, no. 2 (January 16, 2024): 168. http://dx.doi.org/10.3390/cells13020168.
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Mature vascular smooth muscle cells (VSMC) exhibit a remarkable degree of plasticity, a characteristic that has intrigued cardiovascular researchers for decades. Recently, it has become increasingly evident that the chromatin remodeler SWItch/Sucrose Non-Fermentable (SWI/SNF) complex plays a pivotal role in orchestrating chromatin conformation, which is critical for gene regulation. In this review, we provide a summary of research related to the involvement of the SWI/SNF complexes in VSMC and cardiovascular diseases (CVD), integrating these discoveries into the current landscape of epigenetic and transcriptional regulation in VSMC. These novel discoveries shed light on our understanding of VSMC biology and pave the way for developing innovative therapeutic strategies in CVD treatment.
4
Del Savio, Elisa, and Roberta Maestro. "Beyond SMARCB1 Loss: Recent Insights into the Pathobiology of Epithelioid Sarcoma." Cells 11, no. 17 (August 24, 2022): 2626. http://dx.doi.org/10.3390/cells11172626.
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Epithelioid sarcoma (ES) is a very rare and aggressive mesenchymal tumor of unclear origin and uncertain lineage characterized by a prevalent epithelioid morphology. The only recurrent genetic alteration reported in ES as yet is the functional inactivation of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), a key component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes. How SMARCB1 deficiency dictates the clinicopathological characteristics of ES and what other molecular defects concur to its malignant progression is still poorly understood. This review summarizes the recent findings about ES pathobiology, including defects in chromatin remodeling and other signaling pathways and their role as therapeutic vulnerabilities.
5
Wanior, Marek, Andreas Krämer, Stefan Knapp, and Andreas C. Joerger. "Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy." Oncogene 40, no. 21 (May 3, 2021): 3637–54. http://dx.doi.org/10.1038/s41388-021-01781-x.
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AbstractMulti-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. Functional genomic studies revealed a remarkable mutation prevalence of SWI/SNF-encoding genes in 20–25% of all human cancers, frequently driving oncogenic programmes. Some SWI/SNF-mutant cancers are hypersensitive to perturbations in other SWI/SNF subunits, regulatory proteins and distinct biological pathways, often resulting in sustained anticancer effects and synthetic lethal interactions. Exploiting these vulnerabilities is a promising therapeutic strategy. Here, we review the importance of SWI/SNF chromatin remodellers in gene regulation as well as mechanisms leading to assembly defects and their role in cancer development. We will focus in particular on emerging strategies for the targeted therapy of SWI/SNF-deficient cancers using chemical probes, including proteolysis targeting chimeras, to induce synthetic lethality.
6
Soto-Castillo, Juan José, Lucía Llavata-Marti, Roser Fort-Culillas, Pablo Andreu-Cobo, Rafael Moreno, Carles Codony, Xavier García del Muro, Ramon Alemany, Josep M. Piulats, and Juan Martin-Liberal. "SWI/SNF Complex Alterations in Tumors with Rhabdoid Features: Novel Therapeutic Approaches and Opportunities for Adoptive Cell Therapy." International Journal of Molecular Sciences 24, no. 13 (July 6, 2023): 11143. http://dx.doi.org/10.3390/ijms241311143.
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The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy.
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Hasan, Nesrin, and Nita Ahuja. "The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer." Cancers 11, no. 12 (November 25, 2019): 1859. http://dx.doi.org/10.3390/cancers11121859.
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Pancreatic cancer is an aggressive cancer with low survival rates. Genetic and epigenetic dysregulation has been associated with the initiation and progression of pancreatic tumors. Multiple studies have pointed to the involvement of aberrant chromatin modifications in driving tumor behavior. ATP-dependent chromatin remodeling complexes regulate chromatin structure and have critical roles in stem cell maintenance, development, and cancer. Frequent mutations and chromosomal aberrations in the genes associated with subunits of the ATP-dependent chromatin remodeling complexes have been detected in different cancer types. In this review, we summarize the current literature on the genomic alterations and mechanistic studies of the ATP-dependent chromatin remodeling complexes in pancreatic cancer. Our review is focused on the four main subfamilies: SWItch/sucrose non-fermentable (SWI/SNF), imitation SWI (ISWI), chromodomain-helicase DNA-binding protein (CHD), and INOsitol-requiring mutant 80 (INO80). Finally, we discuss potential novel treatment options that use small molecules to target these complexes.
8
Collingwood, TN, FD Urnov, and AP Wolffe. "Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription." Journal of Molecular Endocrinology 23, no. 3 (December 1, 1999): 255–75. http://dx.doi.org/10.1677/jme.0.0230255.
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A contemporary view of hormone action at the transcriptional level requires knowledge of the transcription factors including the hormone receptor that may bind to promoters or enhancers, together with the chromosomal context within which these regulatory proteins function. Nuclear receptors provide the best examples of transcriptional control through the targeted recruitment of large protein complexes that modify chromosomal components and reversibly stabilize or destabilize chromatin. Ligand-dependent recruitment of transcriptional coactivators destabilizes chromatin by mechanisms including histone acetylation and contacts with the basal transcriptional machinery. In contrast, the recruitment of corepressors in the absence of ligand or in the presence of hormone antagonists serves to stabilize chromatin by the targeting of histone deacetylases. Both activation and repression require the action of other chromatin remodeling engines of the switch 2/sucrose non-fermentable 2 (SWI2/SNF2) class. Here we summarize this information and integrate hormone action into a chromatin context.
9
Padilla-Benavides, Teresita, Pablo Reyes-Gutierrez, and Anthony N. Imbalzano. "Regulation of the Mammalian SWI/SNF Family of Chromatin Remodeling Enzymes by Phosphorylation during Myogenesis." Biology 9, no. 7 (July 3, 2020): 152. http://dx.doi.org/10.3390/biology9070152.
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Myogenesis is the biological process by which skeletal muscle tissue forms. Regulation of myogenesis involves a variety of conventional, epigenetic, and epigenomic mechanisms that control chromatin remodeling, DNA methylation, histone modification, and activation of transcription factors. Chromatin remodeling enzymes utilize ATP hydrolysis to alter nucleosome structure and/or positioning. The mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) family of chromatin remodeling enzymes is essential for myogenesis. Here we review diverse and novel mechanisms of regulation of mSWI/SNF enzymes by kinases and phosphatases. The integration of classic signaling pathways with chromatin remodeling enzyme function impacts myoblast viability and proliferation as well as differentiation. Regulated processes include the assembly of the mSWI/SNF enzyme complex, choice of subunits to be incorporated into the complex, and sub-nuclear localization of enzyme subunits. Together these processes influence the chromatin remodeling and gene expression events that control myoblast function and the induction of tissue-specific genes during differentiation.
10
Wu, Shuai, Nail Fatkhutdinov, Leah Rosin, Jennifer M. Luppino, Osamu Iwasaki, Hideki Tanizawa, Hsin-Yao Tang, et al. "ARID1A spatially partitions interphase chromosomes." Science Advances 5, no. 5 (May 2019): eaaw5294. http://dx.doi.org/10.1126/sciadv.aaw5294.
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ARID1A, a subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex, localizes to both promoters and enhancers to influence transcription. However, the role of ARID1A in higher-order spatial chromosome partitioning and genome organization is unknown. Here, we show that ARID1A spatially partitions interphase chromosomes and regulates higher-order genome organization. The SWI/SNF complex interacts with condensin II, and they display significant colocalizations at enhancers. ARID1A knockout drives the redistribution of condensin II preferentially at enhancers, which positively correlates with changes in transcription. ARID1A and condensin II contribute to transcriptionally inactive B-compartment formation, while ARID1A weakens the border strength of topologically associated domains. Condensin II redistribution induced by ARID1A knockout positively correlates with chromosome sizes, which negatively correlates with interchromosomal interactions. ARID1A loss increases the trans interactions of small chromosomes, which was validated by three-dimensional interphase chromosome painting. These results demonstrate that ARID1A is important for large-scale genome folding and spatially partitions interphase chromosomes.
11
Cruz-Tapia, Roberto Onner, Ana María Cano-Valdez, Abelardo Meneses-García, Lorena Correa-Arzate, Adriana Molotla-Fragoso, Guillermo Villagómez-Olea, Diana Brisa Sevilla-Lizcano, and Javier Portilla-Robertson. "Switch/Sucrose Non-Fermentable (SWI/SNF) Complex—Partial Loss in Sinonasal Squamous Cell Carcinoma: A High-Grade Morphology Impact and Progression." Current Issues in Molecular Biology 46, no. 11 (October 30, 2024): 12183–95. http://dx.doi.org/10.3390/cimb46110723.
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Sinonasal carcinomas are aggressive neoplasms that present a high morbidity and mortality rate with an unfavorable prognosis. This group of tumors exhibits morphological and genetic diversity. Genetic and epigenetic alterations in these neoplasms are the current targets for diagnosis and treatment. The most common type of cancer originating in the sinonasal tract is sinonasal squamous cell carcinomas (SNSCCs), which present different histological patterns and variable histological aggressiveness. A significant number of alterations have been reported in sinonasal tumors, including deficiencies in the Switch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex. In the sinonasal tract, deficiencies of the subunits SMARCB1/INI1, SMARCA4/BRG1, and SMARCA2 have been noted in carcinomas, adenocarcinomas, and soft tissue tumors with a distinctive high-grade morphology and a fatal prognosis. Objective: The objective of this study is to identify the status of the SWI/SNF complex using immunohistochemistry in sinonasal squamous cell carcinomas and their association with morphology and survival. Methods: A total of 103 sinonasal carcinomas with different grades of squamous differentiation were analyzed; the selection was based on those cases with high-grade morphology. The carcinomas were then evaluated immunohistochemically for SMARCB1 and SMARCA4 proteins. Their expression was compared with the biological behavior and survival of the patients. Results: Among the SNSCCs, 47% corresponded to the non-keratinizing squamous cell carcinoma (NKSCC) type with high-grade characteristics, 40% were keratinizing squamous cell carcinomas (KSCCs), 9% were SMARCB1-deficient carcinomas, and 4% were SMARCA4-deficient carcinomas. Mosaic expression for SMARCB1 (NKSCC—33%; KSCC—21.9%) and SMARCA4 (NKSCC—14.6%; KSCC—12.2%) was identified, showing an impact on tumor size and progression. Conclusions: We identified that that the partial loss (mosaic expression) of SMARCB1 in SNSCCs is associated with high-grade malignant characteristics and a negative effect on patient survival; meanwhile, SMARCA4-mosaic expression in SNSCCs is associated with high-grade malignant characteristics and an increase in tumor size concerning the intact SMARCA4.
12
Ngo, Carine, and Sophie Postel-Vinay. "Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments." Biomedicines 10, no. 3 (March 11, 2022): 650. http://dx.doi.org/10.3390/biomedicines10030650.
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Mutations in subunits of the SWItch Sucrose Non-Fermentable (SWI/SNF) complex occur in 20% of all human tumors. Among these, the core subunit SMARCB1 is the most frequently mutated, and SMARCB1 loss represents a founder driver event in several malignancies, such as malignant rhabdoid tumors (MRT), epithelioid sarcoma, poorly differentiated chordoma, and renal medullary carcinoma (RMC). Intriguingly, SMARCB1-deficient pediatric MRT and RMC have recently been reported to be immunogenic, despite their very simple genome and low tumor mutational burden. Responses to immune checkpoint inhibitors have further been reported in some SMARCB1-deficient diseases. Here, we will review the preclinical data and clinical data that suggest that immunotherapy, including immune checkpoint inhibitors, may represent a promising therapeutic strategy for SMARCB1-defective tumors. We notably discuss the heterogeneity that exists among the spectrum of malignancies driven by SMARCB1-loss, and highlight challenges that are at stake for developing a personalized immunotherapy for these tumors, notably using molecular profiling of the tumor and of its microenvironment.
13
Luo, Qingyu, Xiaowei Wu, Wan Chang, Pengfei Zhao, Xiaolin Zhu, Hongyan Chen, Yabing Nan, et al. "ARID1A Hypermethylation Disrupts Transcriptional Homeostasis to Promote Squamous Cell Carcinoma Progression." Cancer Research 80, no. 3 (February 1, 2020): 406–17. http://dx.doi.org/10.1158/0008-5472.can-18-2446.
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Abstract Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complexes have a mutation rate of approximately 20% in human cancer, and ARID1A is the most frequently mutated component. However, some components of SWI/SNF complexes, including ARID1A, exhibit a very low mutation rate in squamous cell carcinoma (SCC), and their role in SCC remains unknown. Here, we demonstrate that the low expression of ARID1A in SCC is the result of promoter hypermethylation. Low levels of ARID1A were associated with a poor prognosis. ARID1A maintained transcriptional homeostasis through both direct and indirect chromatin-remodeling mechanisms. Depletion of ARID1A activated an oncogenic transcriptome that drove SCC progression. The anti-inflammatory natural product parthenolide was synthetically lethal to ARID1A-depleted SCC cells due to its inhibition of both HDAC1 and oncogenic signaling. These findings support the clinical application of parthenolide to treat patients with SCC with low ARID1A expression. Significance: This study reveals novel inactivation mechanisms and tumor-suppressive roles of ARID1A in SCC and proposes parthenolide as an effective treatment for patients with SCC with low ARID1A expression.
14
Li, Jing Jing, and Cheok Soon Lee. "The Role of the AT-Rich Interaction Domain 1A Gene (ARID1A) in Human Carcinogenesis." Genes 15, no. 1 (December 19, 2023): 5. http://dx.doi.org/10.3390/genes15010005.
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The switch/sucrose non-fermentable (SWI/SNF) (SWI/SNF) complex uses energy from ATP hydrolysis to mobilise nucleosomes on chromatin. Components of SWI/SNF are mutated in 20% of all human cancers, of which mutations in AT-rich binding domain protein 1A (ARID1A) are the most common. ARID1A is mutated in nearly half of ovarian clear cell carcinoma and around one-third of endometrial and ovarian carcinomas of the endometrioid type. This review will examine in detail the molecular functions of ARID1A, including its role in cell cycle control, enhancer regulation, and the prevention of telomerase activity. ARID1A has key roles in the maintenance of genomic integrity, including DNA double-stranded break repair, DNA decatenation, integrity of the cohesin complex, and reduction in replication stress, and is also involved in mismatch repair. The role of ARID1A loss in the pathogenesis of some of the most common human cancers is discussed, with a particular emphasis on gynaecological cancers. Finally, several promising synthetic lethal strategies, which exploit the specific vulnerabilities of ARID1A-deficient cancer cells, are briefly mentioned.
15
El Hadidy and Uversky. "Intrinsic Disorder of the BAF Complex: Roles in Chromatin Remodeling and Disease Development." International Journal of Molecular Sciences 20, no. 21 (October 23, 2019): 5260. http://dx.doi.org/10.3390/ijms20215260.
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The two-meter-long DNA is compressed into chromatin in the nucleus of every cell, which serves as a significant barrier to transcription. Therefore, for processes such as replication and transcription to occur, the highly compacted chromatin must be relaxed, and the processes required for chromatin reorganization for the aim of replication or transcription are controlled by ATP-dependent nucleosome remodelers. One of the most highly studied remodelers of this kind is the BRG1- or BRM-associated factor complex (BAF complex, also known as SWItch/sucrose non-fermentable (SWI/SNF) complex), which is crucial for the regulation of gene expression and differentiation in eukaryotes. Chromatin remodeling complex BAF is characterized by a highly polymorphic structure, containing from four to 17 subunits encoded by 29 genes. The aim of this paper is to provide an overview of the role of BAF complex in chromatin remodeling and also to use literature mining and a set of computational and bioinformatics tools to analyze structural properties, intrinsic disorder predisposition, and functionalities of its subunits, along with the description of the relations of different BAF complex subunits to the pathogenesis of various human diseases.
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Hu, Xiaolong, Mengjie Li, Xue Hao, Yi Lu, Lei Zhang, and Geng Wu. "The Osa-Containing SWI/SNF Chromatin-Remodeling Complex Is Required in the Germline Differentiation Niche for Germline Stem Cell Progeny Differentiation." Genes 12, no. 3 (March 4, 2021): 363. http://dx.doi.org/10.3390/genes12030363.
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The Drosophila ovary is recognized as a powerful model to study stem cell self-renewal and differentiation. Decapentaplegic (Dpp) is secreted from the germline stem cell (GSC) niche to activate Bone Morphogenic Protein (BMP) signaling in GSCs for their self-renewal and is restricted in the differentiation niche for daughter cell differentiation. Here, we report that Switch/sucrose non-fermentable (SWI/SNF) component Osa depletion in escort cells (ECs) results in a blockage of GSC progeny differentiation. Further molecular and genetic analyses suggest that the defective germline differentiation is partially attributed to the elevated dpp transcription in ECs. Moreover, ectopic Engrailed (En) expression in osa-depleted ECs partially contributes to upregulated dpp transcription. Furthermore, we show that Osa regulates germline differentiation in a Brahma (Brm)-associated protein (BAP)-complex-dependent manner. Additionally, the loss of EC long cellular processes upon osa depletion may also partly contribute to the germline differentiation defect. Taken together, these data suggest that the epigenetic factor Osa plays an important role in controlling EC characteristics and germline lineage differentiation.
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Crodian, Jennifer S., Bethany M. Weldon, Yu-Chun Tseng, Birgit Cabot, and Ryan Cabot. "Nuclear trafficking dynamics of Bromodomain-containing protein 7 (BRD7), a switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex subunit, in porcine oocytes and cleavage-stage embryos." Reproduction, Fertility and Development 31, no. 9 (2019): 1497. http://dx.doi.org/10.1071/rd19030.
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In the work presented here, we investigated how bromodomain-containing protein 7 (BRD7), a subunit associated with switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complexes, is trafficked between cellular compartments during embryo development. SWI/SNF complexes are multi-subunit complexes that contain a core catalytic subunit (SWI/SNF related, Matrix associated, Actin dependent Regulator of Chromatin, subfamily A, member 4, or member 2; SMARCA4 or SMARCA2) and a collection of additional subunits that guide the complexes to their appropriate loci; BRD7 is one of these additional subunits. We hypothesised that BRD7 is exported from the nuclei of porcine oocytes and embryos in a Chromosome Region Maintenance 1 (CRM1)-dependent manner and imported into the nuclei using the karyopherin α/β1 heterodimer. Porcine oocytes and embryos were treated with inhibitors of CRM1-mediated nuclear export and karyopherin α/β1-mediated nuclear import to test this hypothesis. An RNA interference assay and a dominant negative overexpression assay were also performed to determine if karyopherin α7 serves a specific role in BRD7 trafficking. Our findings indicate that BRD7 shuttles between nuclear and cytoplasmic compartments during cleavage development. The shuttling of BRD7 indicates that it serves a unique role in remodelling chromatin during this developmental window.
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Kang, Jong-Seol, Dongha Kim, Joonwoo Rhee, Ji-Yun Seo, Inkuk Park, Ji-Hoon Kim, Daewon Lee, et al. "Baf155 regulates skeletal muscle metabolism via HIF-1a signaling." PLOS Biology 21, no. 7 (July 21, 2023): e3002192. http://dx.doi.org/10.1371/journal.pbio.3002192.
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During exercise, skeletal muscle is exposed to a low oxygen condition, hypoxia. Under hypoxia, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is stabilized and induces expressions of its target genes regulating glycolytic metabolism. Here, using a skeletal muscle-specific gene ablation mouse model, we show that Brg1/Brm-associated factor 155 (Baf155), a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is essential for HIF-1α signaling in skeletal muscle. Muscle-specific ablation of Baf155 increases oxidative metabolism by reducing HIF-1α function, which accompanies the decreased lactate production during exercise. Furthermore, the augmented oxidation leads to high intramuscular adenosine triphosphate (ATP) level and results in the enhancement of endurance exercise capacity. Mechanistically, our chromatin immunoprecipitation (ChIP) analysis reveals that Baf155 modulates DNA-binding activity of HIF-1α to the promoters of its target genes. In addition, for this regulatory function, Baf155 requires a phospho-signal transducer and activator of transcription 3 (pSTAT3), which forms a coactivator complex with HIF-1α, to activate HIF-1α signaling. Our findings reveal the crucial role of Baf155 in energy metabolism of skeletal muscle and the interaction between Baf155 and hypoxia signaling.
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Peinado, Paola, Alvaro Andrades, Marta Cuadros, Maria Isabel Rodriguez, Isabel F. Coira, Daniel J. Garcia, Juan Carlos Álvarez-Perez, et al. "Comprehensive Analysis of SWI/SNF Inactivation in Lung Adenocarcinoma Cell Models." Cancers 12, no. 12 (December 10, 2020): 3712. http://dx.doi.org/10.3390/cancers12123712.
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Mammalian SWI/SNF (SWitch/Sucrose Non-Fermentable) complexes are ATP-dependent chromatin remodelers whose subunits have emerged among the most frequently mutated genes in cancer. Studying SWI/SNF function in cancer cell line models has unveiled vulnerabilities in SWI/SNF-mutant tumors that can lead to the discovery of new therapeutic drugs. However, choosing an appropriate cancer cell line model for SWI/SNF functional studies can be challenging because SWI/SNF subunits are frequently altered in cancer by various mechanisms, including genetic alterations and post-transcriptional mechanisms. In this work, we combined genomic, transcriptomic, and proteomic approaches to study the mutational status and the expression levels of the SWI/SNF subunits in a panel of 38 lung adenocarcinoma (LUAD) cell lines. We found that the SWI/SNF complex was mutated in more than 76% of our LUAD cell lines and there was a high variability in the expression of the different SWI/SNF subunits. These results underline the importance of the SWI/SNF complex as a tumor suppressor in LUAD and the difficulties in defining altered and unaltered cell models for the SWI/SNF complex. These findings will assist researchers in choosing the most suitable cellular models for their studies of SWI/SNF to bring all of its potential to the development of novel therapeutic applications.
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Angelico, Giuseppe, Giulio Attanasio, Lorenzo Colarossi, Cristina Colarossi, Matteo Montalbano, Eleonora Aiello, Federica Di Vendra, Marzia Mare, Nicolas Orsi, and Lorenzo Memeo. "ARID1A Mutations in Gastric Cancer: A Review with Focus on Clinicopathological Features, Molecular Background and Diagnostic Interpretation." Cancers 16, no. 11 (May 30, 2024): 2062. http://dx.doi.org/10.3390/cancers16112062.
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AT-rich interaction domain 1 (ARID1A) is a pivotal gene with a significant role in gastrointestinal tumors which encodes a protein referred to as BAF250a or SMARCF1, an integral component of the SWI/SNF (SWItch/sucrose non-fermentable) chromatin remodeling complex. This complex is instrumental in regulating gene expression by modifying the structure of chromatin to affect the accessibility of DNA. Mutations in ARID1A have been identified in various gastrointestinal cancers, including colorectal, gastric, and pancreatic cancers. These mutations have the potential to disrupt normal SWI/SNF complex function, resulting in aberrant gene expression and potentially contributing to the initiation and progression of these malignancies. ARID1A mutations are relatively common in gastric cancer, particularly in specific adenocarcinoma subtypes. Moreover, such mutations are more frequently observed in specific molecular subtypes, such as microsatellite stable (MSS) cancers and those with a diffuse histological subtype. Understanding the presence and implications of ARID1A mutations in GC is of paramount importance for tailoring personalized treatment strategies and assessing prognosis, particularly given their potential in predicting patient response to novel treatment strategies including immunotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors.
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Ma, Yue, Natisha R. Field, Tao Xie, Sarina Briscas, Emily G. Kokinogoulis, Tali S. Skipper, Amani Alghalayini, et al. "Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies—Therapeutic Vulnerabilities in Treatment-Resistant Subtypes." Cancers 16, no. 17 (September 3, 2024): 3068. http://dx.doi.org/10.3390/cancers16173068.
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SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.
22
Xiao, Lanbo, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, et al. "Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer." Nature 601, no. 7893 (December 22, 2021): 434–39. http://dx.doi.org/10.1038/s41586-021-04246-z.
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AbstractThe switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.
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Ito, Taiji, Hirotaka Watanabe, Nobutake Yamamichi, Shunsuke Kondo, Toshio Tando, Takeshi Haraguchi, Taketoshi Mizutani, et al. "Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54nrb." Biochemical Journal 411, no. 1 (March 13, 2008): 201–9. http://dx.doi.org/10.1042/bj20071075.
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We report that a DBHS (Drosophila behaviour, human splicing) family protein, p54nrb, binds both BRG1 (Brahma-related gene 1) and Brm (Brahma), catalytic subunits of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodelling complex, and also another core subunit of this complex, BAF60a. The N-terminal region of p54nrb is sufficient to pull-down other core subunits of the SWI/SNF complex, suggesting that p54nrb binds SWI/SNF-like complexes. PSF (polypyrimidine tract-binding protein-associated splicing factor), another DBHS family protein known to directly bind p54nrb, was also found to associate with the SWI/SNF-like complex. When sh (short hairpin) RNAs targeting Brm were retrovirally expressed in a BRG1-deficient human cell line (NCI-H1299), the resulting clones showed down-regulation of the TERT (telomerase reverse transcriptase) gene and an enhancement of ratios of exon-7-and-8-excluded TERT mRNA that encodes a β-site-deleted inactive protein. All of these clones display growth arrest within 2 months of the Brm-knockdown. In NCI-H1299 cells, Brm, p54nrb, PSF and RNA polymerase II phosphorylated on CTD (C-terminal domain) Ser2 specifically co-localize at a region incorporating an alternative splicing acceptor site of TERT exon 7. These findings suggest that, at the TERT gene locus in human tumour cells containing a functional SWI/SNF complex, Brm, and possibly BRG1, in concert with p54nrb, would initiate efficient transcription and could be involved in the subsequent splicing of TERT transcripts by accelerating exon-inclusion, which partly contributes to the maintenance of active telomerase.
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Krishnamurthy, Nithya, Shumei Kato, Scott Lippman, and Razelle Kurzrock. "Chromatin remodeling (SWI/SNF) complexes, cancer, and response to immunotherapy." Journal for ImmunoTherapy of Cancer 10, no. 9 (September 2022): e004669. http://dx.doi.org/10.1136/jitc-2022-004669.
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Chromatin regulation involves four subfamilies composed of ATP-dependent multifunctional protein complexes that remodel the way DNA is packaged. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex subfamily mediates nucleosome reorganization and hence activation/repression of critical genes. The SWI/SNF complex is composed of the BRG-/BRM-associated factor and Polybromo-associated BAF complexes, which in turn have multiple subunits. Significantly, ~20% of malignancies harbor alterations in >1 of these subunits, making the genes encoding SWI/SNF family members among the most vulnerable to genomic aberrations in cancer. ARID1A is the largest subunit of the SWI/SNF complex and is altered in ~40%–50% of ovarian clear cell cancers and ~15%–30% of cholangiocarcinomas, in addition to a variety of other malignancies. Importantly, outcome was improved after immune checkpoint blockade (ICB) in patients with ARID1A-altered versuss wild-type tumors, and this result was independent of microsatellite instability or tumor mutational burden. Another subunit—PBRM1—is mutated in ~40% of clear cell renal cell carcinomas and ~12% of cholangiocarcinomas; there are contradictory reports regarding ICB responsiveness. Two other SWI/SNF subunits of interest are SMARCA4 and SMARCB1. SMARCA4 loss is the hallmark of small cell carcinoma of the ovary hypercalcemic type (and is found in a variety of other malignancies); SMARCA4 germline alterations lead to rhabdoid tumor predisposition syndrome-2; SMARCB1 germline alterations, rhabdoid tumor predisposition syndrome-1. Remarkable, although anecdotal, responses to ICB have been reported in both SMARCA4-aberrant and SMARCB1-aberrant advanced cancers. This review focuses on the role that SWI/SNF chromatin remodeling subunits play in carcinogenesis, the immune microenvironment, and in immunotherapy responsiveness.
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Chinnaiyan, Arul M. "Abstract IA021: Targeting epigenetic regulators of oncogenic transcription factors." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): IA021. http://dx.doi.org/10.1158/1538-7445.cancepi22-ia021.
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Abstract The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodeling and is altered in over 20% of cancers. We recently developed and evaluated a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supraphysiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumor growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers. Citation Format: Arul M. Chinnaiyan. Targeting epigenetic regulators of oncogenic transcription factors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA021.
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Xu, Mingyan, Junling Zhang, Xuemei Lu, Fan Liu, Songlin Shi, and Xiaoling Deng. "MiR-199a-5p-Regulated SMARCA4 Promotes Oral Squamous Cell Carcinoma Tumorigenesis." International Journal of Molecular Sciences 24, no. 5 (March 1, 2023): 4756. http://dx.doi.org/10.3390/ijms24054756.
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SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1), an ATPase subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, plays an important regulatory role in many cytogenetic and cytological processes during cancer development. However, the biological function and mechanism of SMARCA4 in oral squamous cell carcinoma (OSCC) remain unclear. The present study aimed to investigate the role of SMARCA4 in OSCC and its potential mechanism. Using a tissue microarray, SMARCA4 expression was found to be highly upregulated in OSCC tissues. In addition, SMARCA4 upregulate expression led to increased migration and invasion of OSCC cells in vitro, as well as tumor growth and invasion in vivo. These events were associated with the promotion of epithelial–mesenchymal transition (EMT). Bioinformatic analysis and luciferase reporter assay confirmed that SMARCA4 is a target gene of microRNA miR-199a-5p. Further mechanistic studies showed that the miR-199a-5p regulated SMARCA4 can promote the invasion and metastasis of tumor cells through EMT. These findings indicate that the miR-199a-5p- SMARCA4 axis plays a role in tumorigenesis by promoting OSCC cell invasion and metastasis through EMT regulation. Our findings provide insights into the role of SMARCA4 in OSCC and the mechanism involved, which may have important implications for therapeutic purposes.
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Wang, Wenjia, Scott C. Friedland, Bing Guo, Michael R. O’Dell, William B. Alexander, Christa L. Whitney-Miller, Diana Agostini-Vulaj, et al. "ARID1A, a SWI/SNF subunit, is critical to acinar cell homeostasis and regeneration and is a barrier to transformation and epithelial-mesenchymal transition in the pancreas." Gut 68, no. 7 (September 18, 2018): 1245–58. http://dx.doi.org/10.1136/gutjnl-2017-315541.
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ObjectiveHere, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.DesignMice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.ResultsArid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation.ConclusionsARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.
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Guo, Ao, Hongling Huang, Zhexin Zhu, Mark J. Chen, Hao Shi, Piyush Sharma, Swantje Liedmann, et al. "The SWI/SNF canonical BAF complex and c-Myc cooperate to promote early fate decisions in CD8+ T cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 169.02. http://dx.doi.org/10.4049/jimmunol.208.supp.169.02.
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Abstract The identification of mechanisms to promote the generation of memory T cells (TMEM) has important implications for vaccination and anti-cancer immunotherapy. Using a CRISPR-based screen for negative regulators of TMEM generation in vivo, we discovered many components of the mammalian canonical SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, also called canonical Brg1/Brg-associated factor (cBAF). cBAF is essential for the differentiation of activated, naïve CD8+ T cells into T effector (TEFF) cells, and loss of cBAF promotes TMEM formation of CD8+ T cells in vivo upon infection with Listeria monocytogenes and influenza A virus (IAV). During the first division of activated CD8+ T cells, we found that cBAF and c-Myc frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high c-Myc are enriched for cBAF expression and display a cell fate trajectory towards TEFF cells, while those with low c-Myc have reduced cBAF, and preferentially differentiate towards TMEM cells. Moreover, the cBAF complex and c-Myc physically interact, and act in concert to establish the chromatin landscape in activated CD8+ T cells. Treatment of naïve CD8+ T cells with an inhibitor of cBAF during the first 48 hours of activation, prior to the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves anti-cancer immunity in a solid tumor model. Our results establish cBAF as a key negative determinant of TMEM cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve adoptive immunotherapy for cancer treatment. Supported by AI123322
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Van Rechem, Capucine. "EPCO-43. CHROMATIN REMODELERS LOST IN TRANSLATION." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii125—vii126. http://dx.doi.org/10.1093/neuonc/noac209.477.
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Abstract The chromatin remodeler complexes mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) are altered in more than 40% of cancers and are involved in therapeutic resistance. In children,SMARCB1 is mutated in 95% of rhabdoid tumors, and the remaining 5% present mutations in SMARCA4. These tumors are typically identified in children younger than three years old and have a very poor prognosis with a survival under one year following diagnosis. SMARCB1 expression is also lost in more than 90% of epithelial sarcomas, a rare and aggressive tumor affecting young adults, and in 50% of pediatric chordomas. Additional mSWI/SNF subunits are also highly mutated in childhood cancers such as ARID1A and ARID1B in neuroblastomas, the most common solid tumor in children, and the ARID subunits and SMARCA4 in medulloblastomas, the most common brain cancer in children. To date, mSWI/SNF roles in normal and cancer cells are still largely undetermined and focus on nuclear functions. However, our assessment of genetic dependencies and drug sensitivity screens revealed that cancer cells mutated for mSWI/SNF are genetically dependent and exclusively sensitive to translation factors and translation pathway inhibitors. We demonstrate that mSWI/SNF complexes are extensively localized in the cytoplasm and that they interact with the translation initiation machinery. Furthermore, short-term inhibition, depletion and cancer mutations of specific subunits alter protein synthesis and increase sensitivity to translation inhibitors. Most mutations in these complexes being considered loss of function, these results suggest a potential therapeutic opportunity for diseases presenting mutations in these complexes. In conclusion, our work demonstrates the chromatin remodelers mSWI/SNF have direct roles in translation that will not only be relevant for the molecular understanding of cancer but also lead to new therapeutic opportunities.
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Van Rechem, Capucine. "BIOL-04. FROM MSWI/SNF’S ROLES IN PROTEIN SYNTHESIS TO NEW THERAPEUTIC OPPORTUNITIES." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i6. http://dx.doi.org/10.1093/neuonc/noad073.023.
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Abstract The chromatin remodeler complexes mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) are altered in more than 40% of cancers and are involved in therapeutic resistance. In children, SMARCB1 is mutated in 95% of rhabdoid tumors, and the remaining 5% present mutations in SMARCA4. These tumors are typically identified in children younger than three years old and have a very poor prognosis with a survival under one year following diagnosis. SMARCB1 expression is also lost in more than 90% of epithelial sarcomas, a rare and aggressive tumor affecting young adults, and in 50% of pediatric chordomas. Additional mSWI/SNF subunits are also highly mutated in childhood cancers such as ARID1A and ARID1B in neuroblastomas, the most common solid tumor in children, and the ARID subunits and SMARCA4 in medulloblastomas, the most common brain cancer in children. To date, mSWI/SNF roles in normal and cancer cells are still largely undetermined and focus on nuclear functions. However, our assessment of genetic dependencies and drug sensitivity screens revealed that cancer cells mutated for mSWI/SNF are genetically dependent and exclusively sensitive to translation factors and translation pathway inhibitors. We demonstrate that mSWI/SNF complexes are extensively localized in the cytoplasm and that they interact with the translation initiation machinery. Furthermore, short-term inhibition, depletion and cancer mutations of specific subunits alter protein synthesis and increase sensitivity to translation inhibitors. Most mutations in these complexes being considered loss of function, these results suggest a potential therapeutic opportunity for diseases presenting mutations in these complexes. In conclusion, our work demonstrates the chromatin remodelers mSWI/SNF have direct roles in translation that will not only be relevant for the molecular understanding of cancer but also lead to new therapeutic opportunities.
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Yao, Xiaosai, Jing Han Hong, Amrita Nargund, and Bin Tean Teh. "Abstract B006: PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B006. http://dx.doi.org/10.1158/1538-7445.cancepi22-b006.
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Abstract Polybromo-1 (PBRM1) is the second most commonly mutated gene in kidney cancer after VHL, occurring at a frequency of 30-40%. PBRM1 loss represents a tumor-initiating event and the combined loss of VHL and PBRM1 is necessary and sufficient for renal malignancy. Functionally, PBRM1 is the defining subunit of the polybromo BRG1-associated factor (PBAF) subclass of SWItch/Sucrose Non-Fermentable (SWI/SNF) remodeling complex which regulates chromatin accessibility by sliding, depositing or evicting nucleosomes. Determining context-specific chromatin remodeling by PBRM1 is paramount to understanding how PBRM1 deficiency drives kidney tumorigenesis. We compared the association of SWI/SNF subunits in the presence or absence of PBRM1 and found that PBRM1 loss resulted in a PBAF complex that has undergone alterations in its configuration and targeting specificity: First, the histone binding lobe disengages from the central ATPase subunit. Second, the PBRM1-deficient complexes, despite retaining the DNA binding lobe, occupy aberrant sites, redistributing from promoter proxy regions to distal enhancer regions. The aberrant sites mapped to regions enriched for NF-κB motifs. Indeed, PBRM1-deficient tumors show enhanced NF-κB activity across isogenic tumor models, genetically modified mouse models and clinical samples. We believe that the PBRM1-deficient PBAF complexes enhance the recruitment of nuclear factor RELA, a subunit of the NF-κB complex - this recruitment requires the ATPase function of the SWI/SNF complexes since BRG1/BRM ATPase inhibitor dampens the expression of NF-κB target genes and RELA chromatin occupancy. Proteasome inhibitor bortezomib reverses NF-κB activity by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, the PBRM1 tumor suppressor safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes. Inhibition of NF-κB activity by bortezomib could be a therapeutic strategy for PBRM1-deficient kidney cancer. Citation Format: Xiaosai Yao, Jing Han Hong, Amrita Nargund, Bin Tean Teh. PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B006.
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Pawel, Bruce R. "SMARCB1-deficient Tumors of Childhood: A Practical Guide." Pediatric and Developmental Pathology 21, no. 1 (December 27, 2017): 6–28. http://dx.doi.org/10.1177/1093526617749671.
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The SMARCB1 gene ( INI1, BAF47) is a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, involved in the epigenetic regulation of gene transcription. SMARCB1 acts as a tumor suppressor gene, and loss of function of both alleles gives rise to SMARCB1-deficient tumors. The prototypical SMARCB1-deficient tumor is the malignant rhabdoid tumor (MRT) which was first described in the kidney but also occurs in soft tissue, viscera, and the brain (where it is referred to as atypical teratoid rhabdoid tumor or AT/RT). These are overwhelmingly tumors of the very young, and most follow an aggressive and ultimately lethal course. Morphologically, most but not all contain a population of “rhabdoid” cells, which are large cells with abundant cytoplasm, perinuclear spherical inclusions, and eccentric vesicular nuclei with large inclusion-like nucleoli. MRT immunohistochemistry reveals complete loss of SMARCB1 nuclear expression, and molecular analysis confirms biallelic SMARCB1 inactivation in the vast majority. Rare AT/RTs have loss of SMARCA4, another SWI/SNF member, rather than SMARCB1. With the widespread adoption of SMARCB1 immunohistochemistry, an increasing number of SMARCB1-deficient tumors outside of the MRT-AT/RT spectrum have been described. In addition to MRT and AT/RT, pediatric tumors with complete loss of SMARCB1 expression include cribriform neuroepithelial tumor, renal medullary carcinoma, and epithelioid sarcoma. Tumors with variable loss of SMARCB1 expression include subsets of epithelioid malignant peripheral nerve sheath tumor, schwannomas arising in schwannomatosis, subsets of chordomas, myoepithelial carcinomas, and sinonasal carcinomas. Variable and reduced expression of SMARCB1 is characteristic of synovial sarcoma. In this review, the historical background, clinical characteristics, morphology, immunohistochemical features, and molecular genetics most germane to these tumors are summarized. In addition, familial occurrence of these tumors (the rhabdoid tumor predisposition syndrome) is discussed. It is hoped that this review may provide practical guidance to pathologists encountering tumors that have altered expression of SMARCB1.
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Gong, Wangqiu, Congwei Luo, Fenfen Peng, Jing Xiao, Yiqun Zeng, Bohui Yin, Xiaowen Chen, et al. "Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis." Clinical Science 135, no. 15 (August 2021): 1873–95. http://dx.doi.org/10.1042/cs20210447.
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Abstract Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWItch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly up-regulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse renal tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished transforming growth factor-β1 (TGF-β1)-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs or normal kidneys increased p16INK4a, p19ARF, and p21 expression and senescence-associated β-galactosidase (SA-β-gal) activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by small interfering RNA (siRNA)-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT-263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin (RAPA)-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1 (Baf A1)-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.
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Halaoui, Adham, Najla Kfoury-Beaumont, and Thomas Beaumont. "Abstract B011: Sex-specific chromatin remodeling drives tumorigenesis in glioblastoma." Cancer Research 84, no. 5_Supplement_1 (March 4, 2024): B011. http://dx.doi.org/10.1158/1538-7445.brain23-b011.
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Abstract SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelling complexes are potent regulators of cellular differentiation that are encoded by some of the most frequently altered genes in cancer. Within this family, the ATP-dependent (BRG-1/BRM associated factor (BAF) chromatin remodelling complex is altered in roughly 20% of human cancers including gliomas. However, its role in gliomagenesis and progression remains largely unknown. The complex exists in three forms: canonical BAF (BAF), polybromo-associated BAF (PBAF) and a non-canonical BAF cmplex (ncBAF), with specific subunits specifying the distinct complexes. We hypothesize a BAF switch as a driver of glioma proliferation and invasiveness. Analysis of 18 human gliomas specimens revealed that BAF complexes were differentially expressed based on World Health Organization (WHO) grade. Specifically, the expression levels of PBAF components (BRD7 and SMARCB1) decreased significantly as WHO grade increased. Conversely, the canonical BAF complex component SMARCE1, and the ncBAF complex component BRD9 were upregulated in high grade vs low grade gliomas. We used CRISPRi to investigate the role of BAF complex in glioblastoma (GBM) tumorigenesis using control and knockdown murine male and female GBM astrocytes. Growth assays demonstrated distinct sex-dependent effects of the three different BAF complex knockouts on GBM astrocyte proliferation. Depletion of SMARCE1 and SMARCB1 resulted in a significant increase in astrocyte growth in male cells, suggesting a potential inhibitory role of canonical BAF in male GBM astrocyte proliferation. Surprisingly, SMARCE1 knockdown led to markedly decreased cell growth in female cells. Knockdown of BRD9 had no effect on proliferation in either male or female GBM cells, suggesting that BRD-9-containing ncBAF may not play a role in the regulation of gliomagenesis. However, knockdown of BRD7 (PBAF) resulted in marked increase in astrocyte growth in both male and female cells. To investigate the clonogenic capacity of the BAF component depleted cells, we performed extreme limiting dilution analysis (ELDA). There was a significant increase in sphere-forming capacity in BRD7 KD cells in both males and females. There was a significant increase in clonogenic frequency in SMARCE1 and SMARCB1 KD in males only, with a significant decrease in sphere formation in SMARCE1 KD in females. Knockdown of BRD9 showed no effect on sphere forming capacity in mouse GBM cells. This data was consistent with tumor cell growth assays and demonstrated a role of BAF in regulation of clonogenic capacity GBM astrocytes.To define the epitranscriptomic effect of BAF complex depletion in GBM cells, we are conducting ChIP- and RNA-seq for the control and BAF depleted GBM cells and characterizing the effect of subunit depletion on BAF complex assembly and composition using affinity purification and mass spectrometry. Understanding the mechanisms underlying the sex-dependent effects of the BAF chromatin remodelling complex in gliomas could be valuable for the development of new precision therapeutics. Citation Format: Adham Halaoui, Najla Kfoury-Beaumont, Thomas Beaumont. Sex-specific chromatin remodeling drives tumorigenesis in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B011.
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Morin, Andrew, Darya Wodetzki, Bethany Veo, Angela Pierce, Shadi Zahedi, Michele Crespo, Sujatha Venkataraman, Rajeev Vibhakar, and Jean Mulcahy-Levy. "ATRT-24. CDK7 Inhibition in AT/RT." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i8. http://dx.doi.org/10.1093/neuonc/noac079.023.
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Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are CNS tumors with a 5-year survival of ~35%. AT/RT is characterized by loss-of-function mutations in the SMARCB1 component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) complex. Based on preliminary CRISPR-Cas9 gene essentiality screen results identifying AT/RT vulnerabilities, we hypothesized that interaction between CDK7 and the SWI/SNF complex via SMARCB1 provides a potential target to improve clinical survival of patients. CDK7 expression was identified by microarray in AT/RT, medulloblastoma, glioblastoma and normal brain. Established cell lines (BT12, BT16, CHLA06), patient derived lines (MAF-737, MAF-1298, MAF-1337), normal human astrocytes (NHA) and NIH3T3 mouse embryonic fibroblast cells were utilized for in vitro response to CDK7 inhibition. Murine cerebellar xenografts of MAF-737 were utilized to evaluate genetic and pharmacologic response to CDK7 inhibition. The NCI Approved Oncology Drugs (AOD-9) Panel was evaluated with an IC25 dose of CDK7 inhibitor THZ2 to identify potential synergistic combinations. CDK7 is up-regulated in AT/RT compared to other brain tumors or normal brain. In vitro, AT/RT cells are highly susceptible to CDK7 pharmacologic inhibition with nM IC50 levels. AT/RT cells with shRNA against CDK7 implanted in vivo show significantly reduced growth. Evaluation of in vivo tumors treated with THZ2 demonstrate decreased Ki-67 and reduced pRBP1 demonstrating effective inhibition of the target as well as a decrease in cell proliferation. Combination therapy of THZ2 with the AOD-9 Panel found significant synergy with antimetabolite therapies, specifically pemetrexed, pralatrexate, and methotrexate. There was no synergy with other standard chemotherapy. Our findings demonstrate that CDK7 is highly expressed in AT/RT and necessary for proliferation of AT/RT cells, suggesting it as a potential therapeutic target. Antimetabolites, which are currently used in several AT/RT protocols, synergized with CDK7 inhibition offers a potential future combination therapy for patients.
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Abraham, Ajay, Daniela Samaniego-Castruita, Jillian Paladino, Mi Thao Tran, Isabella Goeun Han, Prathyaya Ramesh, Heather Kligfeld, Rebecca Southern, Ashima Shukla, and Vipul Shukla. "Loss of SWI/SNF Complex Subunit Arid1a in B Cells Promotes Inflammation and Perturbs Germinal Center B Cell Responses." Blood 142, Supplement 1 (November 28, 2023): 1400. http://dx.doi.org/10.1182/blood-2023-189789.
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The Switch/Sucrose Non-Fermentable (SWI/SNF) complex is a major mediator of nucleosomal remodeling in eukaryotic genomes and plays a crucial role in the regulation of chromatin accessibility and establishment of gene expression programs. SWI/SNF complex is comprised of ~15 protein subunits, many of which are frequently mutated in several solid tumors and hematological malignancies, including B cell lymphomas. Among SWI/SNF subunits, ARID1a, ARID1B, and SMARCA4 are each mutated in ~10% of Diffuse Large B-Cell Lymphomas, which is a germinal center B cell-derived malignancy representing 95% of all adult lymphomas. Germinal Centers (GC) are microanatomical sites in secondary lymphoid tissues where B cells undergo activation and differentiation, however the role of SWI/SNF complex in GC B cell biology and development of GC-derived malignancies has not been studied. To address this, we investigated the role of Arid1a, the core subunit of SWI/SNF complex, in GC B cell differentiation and function. Using genetic mouse models with constitutive ( CD19 Cre) and activation induced ( Cg1 Cre) B cell-specific deletion of Arid1a, our studies revealed that Arid1a is indispensable for the formation of germinal centers . Arid1a-deficient B cells show profound defects in affinity maturation and fail to mount high-affinity antibody responses. However, in contrast, under in vitro conditions mimicking germinal centers, Arid1a-deficient B cells can efficiently undergo activation and class switch recombination, suggesting that Arid1a-deficient B cells are not inherently defective in their ability to proliferate and differentiate in response to stimulation. Interestingly, while Arid1a-deficient activated B cells display a global reduction in chromatin accessibility, this was also accompanied by induction of inflammatory gene and accessibility signatures. A careful examination of B cell-specific Arid1a-deficient mice demonstrated no apparent defects in the initiation of GC response, though, the sustenance of B cells in the GCs was severely compromised. In addition, Arid1a-deficient GC precursors effectively promoted the differentiation of T follicular helper cells, but also enhanced recruitment of inflammatory monocytes and neutrophils at both early and late stages post-immunization, compared to control mice. These studies suggest that Arid1a loss in B cells instigates an inflammatory milieu which may contribute to a pre-mature termination of GC program. Overall, our studies establish a critical role of SWI/SNF complex in GC B cell biology and provides insights for how loss of Arid1a could contribute to pathogenesis of B cell lymphomas. Our work is consistent with recent paradigms highlighting detrimental effects of an inflammatory micro-environment on germinal centers, which is commonly observed in patients with severe bacterial and viral infections.
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Mota, Mateus, Stefan Sweha, Matt Pun, Siva Kumar Natarajan, Yujie Ding, Chan Chung, Debra Hawes, et al. "Abstract PR-007: H3.3K27M diffuse midline gliomas are sensitive to SWI/SNF chromatin remodeler degradation." Cancer Research 84, no. 5_Supplement_1 (March 4, 2024): PR—007—PR—007. http://dx.doi.org/10.1158/1538-7445.brain23-pr-007.
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Abstract Diffuse Midline Gliomas (DMG) including Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain tumor. The lysine 27 (K27)-to-methionine (M) point mutation in histone H3.1 or H3.3 (H3.1K27M or H3.3K27M, respectively) affects about 80% of patients establishing H3K27M mutation as a tumor hallmark. Mutated H3 histones inhibit the function of Polycomb repressive complex 2 resulting in global reduction of repressive H3K27me3. In addition, increased acetylation of H3K27 is observed, further contributing to an aberrant chromatin state. Considering the impact of epigenetic alterations in DIPG, we investigated the role of Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelers in shaping the oncogenic chromatin state in DIPG cells. DIPG cells harboring H3.3K27M mutation were sensitive to combined SMARCA4/SMARCA2/PBRM1 degradation by the proteolysis targeting chimera (PROTAC) AU-15330 degrader. Our premise is based on the SWI/SNF complex altering chromatin states of tumor cells to regulate the tumor immune microenvironment. We hypothesized that the SWI/SNF complex in tumor cells modulates immune responses in DIPG. Cytokine profiler arrays in AU-15330 versus vehicle treated H3.3K27M cells showed a marked decrease of Intercellular Cell Adhesion Molecule-1 (ICAM-1) glycoprotein levels. In addition to its well-known role in leukocyte endothelial transmigration, ICAM-1 contributes to malignant potential of tumor cells. We validated downregulation of ICAM-1 mRNA and protein levels by AU-15330 by immunoblotting, proteomics, and transcriptomics, suggesting an epigenetic regulation of ICAM-1 gene transcription by the SWI/SNF complex. Moreover, silencing of mutant H3.3-encoding gene decreased ICAM-1 protein levels, suggesting ICAM-1 expression is promoted by H3.3K27M mutation-induced SWI/SNF chromatin remodeling in DIPG. In conclusion, our work suggests the H3.3K27M mutation renders DIPG cells dependent on chromatin remodeling by SWI/SNF complexes that can in turn alters the expression of immune system-associated components, such as ICAM-1. Our future work is geared to understanding the role of the SWI/SNF complex in regulating the immune tumor microenvironment in H3K27M DMGs. Citation Format: Mateus Mota, Stefan Sweha, Matt Pun, Siva Kumar Natarajan, Yujie Ding, Chan Chung, Debra Hawes, Fusheng Yang, Alexander Judkins, Susanta Samajdar, Xuhong Cao, Lanbo Xiao, Abhijit Parolia, Arul Chinnaiyan, Sriram Venneti. H3.3K27M diffuse midline gliomas are sensitive to SWI/SNF chromatin remodeler degradation [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-007.
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Basu, Gargi D., Tracey White, Janine R. LoBello, Kevin R. Lau, Michael Syring, Subha Krishnan, Laura Gonzalez, et al. "ARID1A alterations in gastrointestinal cancers as therapeutic opportunities." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 671. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.671.
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671 Background: The gene encoding the AT-rich interacting domain (ARID1A) is a tumor suppressor and a subunit of the Switch/Sucrose Non fermentable (SWI/SNF) chromatin remodeling complex that regulates gene expression. Additionally, ARID1A functions to maintain genomic integrity by interacting with ATR. Mutations in ARID1A have been observed in a number of cancers. Inactivation of ARID1A has been reported to lead to increased sensitivity to inhibitors of PARP and PI3K/AKT pathway. We evaluated ARID1A alterations in gastrointestinal (GI) cancers to identify new therapeutic options. Methods: Comprehensive genomic profiling was performed on 55 GI cancer samples with 28 metastatic and 27 primary samples. Targeted sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA samples. Results: ARID1A alterations were noted in 20% (11/55) of GI cancers. Alterations included frameshift and nonsense mutations, INDELs and structural breakpoints which are predicted to cause loss of ARID1A function. Tumor tissues harboring ARID1A alterations included 2/8 gastro-esophageal cancers, 2/2 duodenal cancers, 3/29 colorectal (CRC) cancers, 2/2 small bowel cancers, and 2/7 bile duct cancers. Mutations in the C-terminal half of ARID1A, known to interact with ATR and mediate its recruitment to double strand breakpoints was present in 2/11 samples. No pathogenic changes in the DNA repair genes (BRCA1/2, CHEK1/2, ATM, ATR or PALB2) or MMR genes were present in the tumors harboring ARID1A alterations. Interestingly, ARID1A mutations frequently coexisted with alterations leading to activation of the PI3K pathway. We found 45% (5/11) samples with mutated ARID1A had pathogenic alterations in PIK3CA, AKT, NF1, STK11, TSC1 and TSC2 genes which may increase sensitivity to PI3K pathway inhibitors. Conclusions: Targeted sequencing demonstrated that ARID1A is a frequent event in GI cancer. Our results suggest there may be a correlation between samples with ARID1A alteration and PI3K/AKT pathway activation which may lead to therapeutic opportunities with PI3K pathway inhibitors. The presence of ARID1A mutations especially those in the C-terminal half may predict clinical utility of PARP inhibitors in GI cancer.
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Elzamly, S., A. Murzabdillaeva, H. Taha, M. Shitawi, and H. Zhu. "SMARCA4 Deficient Thoracic Sarcoma Presenting with a Pathologic Fracture of Proximal Tibia and L5 Vertebral Body: a Case Report and Review of Literature." American Journal of Clinical Pathology 154, Supplement_1 (October 2020): S40—S41. http://dx.doi.org/10.1093/ajcp/aqaa161.085.
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Abstract Introduction/Objective SMARCA4 (BRG1) is a central component of the Switch/Sucrose-Non-Fermentable (SWI/SNF) chromatin remodeling complex which plays a critical role in the initiation, progression and dedifferentiation of a variety of cancers arising in different anatomical sites. The recently discovered SMARCA4-deficient thoracic sarcoma (DTS) can present as a mediastinal, pleural or pulmonary mass and constitutes a unique and highly lethal entity. Methods Here we present an interesting case of a 66-year-old, smoker male with past medical history of COPD, polysubstance abuse, hepatitis C virus, and alcoholic cirrhosis who presented with left proximal tibia pathological fracture, L5 vertebral body lytic lesion, left leg cellulitis and hypercalcemia. Imaging studies, tibia biopsy, thoracocentesis, histopathological examination, and immunohistochemical stains were performed. Results Imaging studies revealed a 3.1 cm, right upper lobe speculated lung mass along with multiple other lung nodules. Numerous arterially enhancing hepatic masses up to 2.8 cm were also identified. The patient underwent intramedullary nail, cementation and tibia biopsy followed by thoracentesis a month later.The histological sections revealed sheets of poorly differentiated malignant epithelioid cells showing high nuclear pleomorphism, prominent nucleoli, eosinophilc cytoplasm with extensive necrosis, and high mitosis (Ki-67 around 100%). The tumor cells lacked the expression of SMARCA4 (BRG1), cytokeratin, SALL4, CD34, TTF-1, P40, S100, HMB45, pan melanoma, desmin, CD31, ERG, CD30, CD56, chromogranin, CD38, CD45, CD3, ALK-1, myeloperoxidase, glypican-3, hepatocyte, and inhibin with mixed kappa and lambda. Tumor cells expressed SATB2 and focal synaptophysin, consistent with SMARCA4 deficient thoracic sarcoma metastasizing to the bone. The patient’s condition rapidly deteriorated and he died within two months. Conclusion An accurate diagnosis of these tumors is paramount and can be challenging. However, recognizing SMARCA4-DTS from other types of epithelioid tumors that involve the thoracic region is clinically relevant, as targeted therapies for SMARC-deficient tumors are currently being investigated and new clinical trial data show therapeutic benefit.
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Parolia, Abhijit, Lanbo Xiao, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Eleanor Young, Rahul Mannan, et al. "Abstract 3592: Targeting SWI/SNF ATPases in enhancer-addicted human cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3592. http://dx.doi.org/10.1158/1538-7445.am2022-3592.
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Abstract In mammalian cells, DNA is wrapped around histone octamers (collectively referred to as nucleosomes) which form a physical barrier to all DNA-based processes. The switch/sucrose non-fermentable (SWI/SNF) is a multi-subunit chromatin remodeling complex that uses energy from ATP hydrolysis to reposition or eject nucleosomes at non-coding regulatory elements, thereby enabling access to the underlying DNA for transcriptional activation. Notably, the SWI/SNF complex plays a crucial role in chromatin remodeling and is recurrently altered in over 20% of human cancers, with the revised complex in cancer cells enabling central oncogenic gene programs. Yet, no studies have assessed the therapeutic efficacy of complete SWI/SNF inactivation across human cancers. Here, we developed a proteolysis targeting chimera (PROTAC) degrader of ATPase subunits of the SWI/SNF complex, SMARCA2 and SMARCA4. In a panel with over 90 normal and cancer cell lines from 18 different lineages, we found MYC-driven multiple myeloma and androgen receptor (AR)/forkhead box A1 (FOXA1)-positive prostate and breast cancers to be preferentially sensitive to dual SMARCA2 and SMARCA4 degradation relative to benign prostate as well as other cancer cell lines, including cancer cell lines with inactivating SMARCA4 mutations. We found complete SWI/SNF ATPase degradation to instantaneously compact the cis-regulatory elements that are bound and activated by transcription factors that drive cancer proliferation, namely MYC, IRF4, TCF3, AR, FOXA1, and ERG. This ensued in parallel untethering of these oncogenic drivers from the chromatin, with subsequent chemical decommissioning of their core enhancer circuitry and attenuation of downstream gene programs. Furthermore, using chromatin conformation assays we found SWI/SNF inactivation to disrupt super-enhancer and promoter DNA looping interactions that wire supra-physiologic expression of the MYC, AR, ERG, IRF4, and TCF3 oncogenes themselves, thereby tempering their expression in cancer cells. Treatment with the SMARCA2/4 degrader alone induced potent inhibition of tumor growth in cell line-derived xenograft models of multiple myeloma, as well as prostate cancer, and synergized with AR antagonists, inducing disease remission in several drug-resistant disease models. Notably, no major toxicities were seen in mice upon prolonged treatment with the SMARCA2/4 degrader, including no indications of thrombocytopenia, gastrointestinal goblet cell depletion, or germ cell degeneration—all being major toxicities associated with the BRD4-targeting therapeutics. To our knowledge, this study is the first preclinical proof of concept that targeted obstruction of chromatin accessibility at non-coding regulatory elements can be a potent therapeutic strategy in enhancer-addicted tumors, warranting the safety and efficacy assessments of SWI/SNF inhibitors and degraders in human clinical trials. Citation Format: Abhijit Parolia, Lanbo Xiao, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Eleanor Young, Rahul Mannan, Sandra E. Carson, Yu Chang, Yuping Zhang, James George, Mustapha Jaber, Fengyun Su, Rui Wang, Sanjita Sasmal, Leena Khare, Subhendu Mukerjee, Chandrasekhar AbbinenI, Kiran Aithal, Xuhong Cao, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra, Arul M. Chinnaiyan. Targeting SWI/SNF ATPases in enhancer-addicted human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3592.
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Xiao, Lanbo, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa Pushpinder, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, et al. "Abstract 5469: Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5469. http://dx.doi.org/10.1158/1538-7445.am2022-5469.
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Abstract The switch/sucrose non-fermentable (SWI/SNF) complex plays a crucial role in chromatin remodeling and is recurrently altered in over 20% of human cancers. Here, we developed a proteolysis targeting chimera (PROTAC) degrader of ATPase subunits of the SWI/SNF complex, SMARCA2 and SMARCA4. Intriguingly, we found androgen receptor (AR)/forkhead box A1 (FOXA1)-positive prostate cancer to be exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to benign prostate as well as other cancer cell lines, including those with inactivating SMARCA4 mutations. Mechanistically, SWI/SNF inhibition rapidly compacts the cis-regulatory elements that are bound and activated by transcription factors that drive cancer proliferation, namely AR, FOXA1, ERG, and MYC. This ensues in chromatin untethering of these oncogenic drivers, chemical decommissioning of their core enhancer circuitry, and attenuation of downstream gene programs. Furthermore, we found SWI/SNF inhibition to disrupt super-enhancer and promoter DNA looping interactions that wire supra-physiologic expression of the AR, FOXA1, and MYC oncogenes, thereby tempering their expression in cancer cells. Monotherapy with the SMARCA2/4 degrader induced potent inhibition of tumor growth in cell line-derived xenograft models of prostate cancer and remarkably synergized with AR antagonists, inducing disease remission in models of castration-resistant prostate cancer. We also found the combinatorial treatment to significantly inhibit the growth of enzalutamide resistant disease using in vitro as well as patient-derived xenograft models. Notably, no major toxicities were seen in mice upon prolonged treatment with the SMARCA2/4 degrader, including no indications of thrombocytopenia, gastrointestinal goblet cell depletion, or germ cell degeneration. Taken together, these results suggest that impeding enhancer accessibility through SWI/SNF ATPase inactivation represents a novel therapeutic approach in enhancer addicted human cancers. Citation Format: Lanbo Xiao, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa Pushpinder, Sanjana Eyunni, Rahul Mannan, Sandra E. Carson, Yu Chang, Xiaoju Wang, Yuping Zhang, Josh Vo, Steven Kregel, Stephanie A. Simko, Andrew D. Delekta, Mustapha Jaber, Heng Zheng, Ingrid Apel, Lisa McMurry, Fengyun Su, Rui Wang, Sylvia Wang, Sanjita Sasmal, Leena K. Satyam, Subhendu Mukherjee, Chandrasekhar AbbinenI, Kiran Aithal, Mital S. Bhakta, Jay Ghurye, Xuhong Cao, Nora M. Navone, Alexey Nesvizhskii, Rohit Mehra, Ulka Vaishampayan, Marco Blanchette, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra, Arul M. Chinnaiyan. Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5469.
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Khosrowjerdi, Sara J., Nora K. Horick, Jeffrey William Clark, Aparna Raj Parikh, Jill N. Allen, Ryan David Nipp, Joseph Wang Franses, et al. "Clinical and mutational profile of ARID1A-mutated gastrointestinal cancers: Duration of response to platinum-based chemotherapy." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15611-e15611. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15611.
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e15611 Background: ARID1A is mutated in several cancer types, with studies reporting mutations in up to 10% of colorectal cancers (CRC) and as high as 35% of gastric and pancreatic cancers. The ARID1A gene encodes a member of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex and functions as a tumor suppressor. ARID1A has also been implicated in double-stranded DNA repair via both homologous recombination and non-homologous end-joining, potentially conferring platinum sensitivity. We sought to characterize this subset of gastrointestinal (GI) malignancies. Methods: We identified patients with locally advanced or metastatic ARID1A-mutated GI malignancies treated at Massachusetts General Hospital (MGH) by next-generation sequencing. Patients were selected who gave consent to molecular testing and who were enrolled on to a study. We evaluated clinical characteristics and outcomes for patients undergoing treatment at MGH between 2009 and May 2020. The Kaplan-Meier method was used to calculate progression free survival (PFS) to first-line platinum-based chemotherapy. Results: We captured 38 patients with ARID1A-mutated tumors. Median age at diagnosis was 66 (range 31-87) and 63.2% of patients were male (n = 24). Tumor types varied, including CRC (n = 13, 34.2%), esophagogastric (n = 13, 34.2%), pancreatic (n = 6, 15.7%), cholangiocarcinoma (n = 2, 5.3%), small bowel (n = 1, 2.6%), anal (n = 1, 2.6%), and unknown GI primary (n = 2, 5.3%). Most were metastatic at diagnosis (n = 23, 60.5%). The identified ARID1A mutations were each distinct, occurring along the length of the gene and were comprised of missense (n = 10, 26.3%), nonsense (n = 12, 31.6%), frameshift (n = 13, 34.2%), and splice-site (n = 3, 7.9%) mutations. We observed on average 4-5 co-mutations per tumor, with TP53 (n = 25, 65.8%), KRAS (n = 14, 36.8%), APC (n = 11, 28.9%), BRCA2 (n = 7, 18.4%) and BRAF (n = 7, 18.4%) occurring most frequently. Tumors were both microsatellite stable (n = 23, 60%) and microsatellite unstable (n = 7, 18.4%). Most patients (n = 37, 97.4%) received a platinum-based chemotherapy as first-line therapy including FOLFOX (n = 23, 60.5%), FOLFIRINOX (n = 10, 26.3%), gemcitabine/cisplatin (n = 2, 5.3%), carboplatin/5-FU (n = 1, 2.6%), and carboplatin/etoposide (n = 1, 2.6%). Median PFS for first-line platinum based chemotherapy was 14.0 months (CI 8.2-34.7) overall. For patients with CRC, PFS to platinum-based therapy was 14.0 months (CI 4.8-not reached) compared with 9.6 months for non-CRC (CI 7.4-not reached). Conclusions: To our knowledge, this is the first assessment of clinical characteristics and outcomes for ARID1A-mutated GI malignancies. Mutations in ARID1A are highly diverse, without a clear association with tumor type. Future studies assessing response to platinum-based chemotherapy are warranted.
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Bajaj, Anubha. "Exiguous and Scarce-SMARCB1 Deficient Medullary Renal Cell Carcinoma." Cell & Cellular Life Sciences Journal 8, no. 2 (2023): 1–4. http://dx.doi.org/10.23880/cclsj-16000188.
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Switch / sucrose non fermentable (SWI/SNF) related, matrix associated, actin dependent regulator of chromatin subfamily B member 1 (SMARCB1) deficient medullary renal cell carcinoma is an exceptionally discerned, aggressive carcinoma associated with deficiency of SMARCB1 or integrase interactor 1(INI1).
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Wedekind, Mary Frances, Srivandana Akshintala, Brigitte C. Widemann, Charles G. Minard, Olga Militano, David Hall, Zanette Bradley, et al. "Phase 1/2 study of tiragolumab and atezolizumab in patients with relapsed or refractory SMARCB1 or SMARCA4 deficient tumors." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): TPS10066. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.tps10066.
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TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .
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Lin, Frank Po-Yen, Subotheni Thavaneswaran, Christine E. Napier, John P. Grady, Maya Kansara, Lucille Sebastian, Damien Kee, et al. "Genomic therapy matching in rare and refractory cancers: Updated results from a retrospective cohort study in the Molecular Screening and Therapeutic (MoST) program." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 1540. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.1540.
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1540 Background: Biomarker actionability and therapy matching are two central concepts in precision oncology. However, the best strategy to align therapy with genomic alterations remains unclear. Here we report the updated results from a cohort study conducted in an Australian precision oncology program (MoST, ACTRN12616000908437), examining a therapy matching strategy based on comprehensive genomic profiling (CGP) results. Methods: All patients (pts) with rare or advanced solid tumours undergoing CGP from 2016 to 2021 after exhausting standard treatments were included. The primary outcome was overall survival (OS) from the date of CGP result, estimated using the Kaplan-Meier method. Pts were grouped according to tiers of actionability determined by matching against the TOPOGRAPH knowledge base ( https://topograph.info ) and stratified into clinically active (Tier 1-3, therapies with evidence from prospective trials), investigational (Tier 3B and 4, therapies with evidence from another cancer type, preclinical, or retrospective studies), or unmatched tier groups. To assess between-group differences in OS, hazard ratios (HR) were estimated in a time-varying Cox regression model adjusting for time to initiation of subsequent therapy. Results: This updated analysis included 3,383 pts (79% rare and less common). The median follow-up was 22.6 months (mo). For 2,065 pts who did not receive treatment after CGP, the median OS (mOS) was 8.2 mo (95% CI 7.4 to 9.0). For 1,318 pts who received ≥1 line of therapy after CGP, the mOS was 14.1 mo (13.4 to 15.2). 1,270 pts (38%) carried a genomic alteration linked to clinically active therapies (Tier 1-3). Of these, 116 (3.4%) received matched treatment after CGP, experiencing longer survival compared with 410 (32.2%) that received only unmatched therapy (mOS 21.2 v 12.8 mo, HR 0.58, 0.45 to 0.76, P<0.001). Whilst receiving a matched therapy in the investigational tier group (n=133, T3B/4) did not show significant differences in outcomes (mOS 14.5 v unmatched 12.8 mo, n=536, HR 0.88, 0.72 to 1.08, p=0.24), exploratory analyses identified differences in survival for a subset of 41 pts with Switch/Sucrose Non-Fermentable complex mutations receiving matched Tier 4 therapies (mOS 30.1 v 9.6 mo, HR 0.29, 0.17 to 0.51, P<0.0001). Pts receiving repurposed drugs that matched solely on biomarkers in non-cognate cancer types (Tier 3B) showed no survival difference over unmatched therapy (n=35 v 469, mOS 13.6 v 12.5 mo, HR 0.96, 0.65 to 1.41, p=0.83). Conclusions: This study provides insight into how biomarker-linked therapies can be rationally prioritised in rare and advanced cancer populations. Addressing the barriers of access to Tier 1-3 therapies may broaden the utility of genomic biomarker testing. Off-label drug repurposing without direct supporting evidence should only be undertaken in a clinical trial setting.
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Ho, Rebecca, Eunice Li, Chae Young Shin, Shary Chen, David Huntsman, and Yemin Wang. "Abstract 7061: Targeting metabolic vulnerabilities in ARID1A/B dual-deficient dedifferentiated endometrial carcinoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 7061. http://dx.doi.org/10.1158/1538-7445.am2024-7061.
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Abstract Background: Dedifferentiated endometrial carcinoma (DDEC) is an aggressive endometrial carcinoma defined histologically by undifferentiated carcinoma juxtaposed against stage 1 or 2 endometrial adenocarcinoma. DDEC responds poorly to conventional platinum/taxane-based chemotherapy, particularly in the case of extrauterine spread. This highlights a need to develop novel therapies for individuals with DDEC. Genetically, a third of DDEC cases have co-inactivating mutations of ARID1A and ARID1B. These genes encode core subunits of the sucrose/switch non-fermentable (SWI/SNF) complex that regulate transcription. Furthermore, dual loss of ARID1A/B is believed to play a role in driving DDEC tumor development. We hypothesize that ARID1A/B dual-deficiency in DDEC generates unique genetic deficiencies that allow for the development of novel therapies for this cancer. We approached this hypothesis by first conducting a preliminary analysis of the Cancer Dependency Map (DepMap), which has identified vulnerabilities in mitochondrial functioning in ARID1A/B dual-deficient DDECs. As such, we aimed to understand the role of mitochondrial oxidative phosphorylation (OXPHOS) and redox homeostasis in ARID1A/B dual-deficient DDEC to create new treatment options. Methods: A panel of ARID1A/B dual-deficient and proficient endometrial cancer cell lines were treated with OXPHOS inhibitor IACS-010759 and reactive oxidative species (ROS)-inducing agent elesclomol to identify shifts in drug response between the two groups. To account for genomic differences between the cell lines, we also treated an ARID1B knock-out isogeneic cell line with the drugs. Additionally, changes in metabolism in the endometrial cancer cell lines were measured using Seahorse metabolic flux assays to determine if ARID1A/B dual-deficient cell lines have an increased dependency on OXPHOS for cell growth. Results: While the Seahorse assays revealed no significant difference in OXPHOS and glycolysis activities between the two groups, drug sensitivity assays demonstrated that ARID1A/B dual-deficient cancers are more sensitive to OXPHOS inhibition and increased ROS production than the proficient cell lines. Depletion of ARID1B in an ARID1A deficient cell line sensitizes the cells to both drugs. Furthermore, IACS-010759 significantly suppressed the growth of ARID1A/B-deficient DDEC xenograft tumor growth. Conclusion: ARID1A/B-dual deficient cancer cells rely on mitochondria function for survival. The underlying mechanisms are currently under investigation. Citation Format: Rebecca Ho, Eunice Li, Chae Young Shin, Shary Chen, David Huntsman, Yemin Wang. Targeting metabolic vulnerabilities in ARID1A/B dual-deficient dedifferentiated endometrial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7061.
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Modemann, Franziska, Leoni Ramke, Erkin Erdal, Melanie Schoof, Carolin Göbel, Sina Neyazi, Carsten Bokemeyer, Jasmin Wellbrock, Ulrich Schüller, and Walter Fiedler. "Loss of SMARCA4 Leads to an Impaired Hematopoiesis in Mice." Blood 142, Supplement 1 (November 28, 2023): 1377. http://dx.doi.org/10.1182/blood-2023-178137.
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SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a) is the central ATPase containing enzyme in the SWI/SNF- (switch/sucrose non-fermentable) complex, which regulates chromatin accessibility and thereby influences gene transcription. By acting as a transcriptional activator or repressor in different cell types, SMARCA4 and the SWI/SNF complex have various functions. Our aim was to understand the function of SMARCA4 in healthy hematopoiesis in order to then apply our findings to different hematologic diseases in a second step. To investigate the role of SMARCA4 in haematopoiesis and hematopoietic stem cells, we created a transgenic Smarca4 knockout mouse model. An inducible knockout system was chosen since early embryonic knockout of SMARCA4, which is crucially involved in embryonic development leads to a lethal phenotype. The Cre/loxP system was used to induce homozygous Smarca4 knockout under the control of the hematopoiesis-specific promotor Mx-1. We then performed blood counts, bone marrow smears and RNA sequencing, including analysis of RNA signature of the different cell types in the bone marrow to decipher the composition of the bone marrow of Smarca 4 deficient mice. Blood count analysis showed that Smarca4 knockout mice have significantly lower leukocyte, reticulocyte, and thrombocyte counts. In addition, bone marrow showed lower colony forming capacity in colony formation assays compared to healthy cre-negative control mice. Bone marrow smears displayed aplasia of all cell lines in Smarca4 knockout mice with additional signs of dysplasia as hypolobulatedmegakaryocytes or nuclear blasts. RNA-sequencing revealed 749 upregulated and 520 downregulated genes with a log fold change ≥ +/- 1 in the bone marrow of Smarca4 knockout mice compared to cre-negative control mice. Relevant over represented pathways according to REACTOME data base included genes of generation of second messenger molecules, cell surface interactions at the vascular wall, and immunoregulatory interactions between lymphoid and non-lymphoid cells. Through cell type deconvolution (CIBERSORTx) of the bulk microarray gene expression data we estimated abundances for different cell types. Results revealed a decrease in granulocyte and macrophage progenitors (statistically significant) as well as in eosinophil progenitor cells, and in erythroid pre-colony forming units. Interestingly, both common myeloid and common lymphoid progenitors were increased. It seems as if the progenitor cells accumulate and take a different path when Smarca4 is knocked out in these cells (figure 2). We conclude that SMARCA4 is crucial for cell growth and differentiation of progenitor cells in the bone marrow during hematopoiesis since a Smarca4 knockout leads to differentiation arrest and accumulation of distinct progenitor cells and pancytopenia in peripheral blood. Figure 1: Abundances for 23 cell populations in Smarca4 knockout (KO) and wildtype (WT) samples were estimated using CIBERSORTx. Bubble plot showing Log2 fold changes of average abundances in KO vs WT with accumulation of distinct progenitor cells in the bone marrow of Smarca4 deficient mice. As underlying signature-matrix the haemopedia gene set was used. Bubbles with black borders indicate significance of difference between samples.
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Ma, Yue, Kristie Ann Dickson, Natisha Field, Tao Xie, Nham Tran, and Deborah Joy Marsh. "Abstract A038: Epigenetic compound library screen of ovarian clear cell carcinoma cell line models identifies decreased cell viability following treatment with the Bruton tyrosine kinase inhibitor ibrutinib." Cancer Research 84, no. 5_Supplement_2 (March 4, 2024): A038. http://dx.doi.org/10.1158/1538-7445.ovarian23-a038.
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Abstract Ovarian clear cell carcinoma (OCCC) is a difficult to treat histological subtype of ovarian cancer, demonstrating resistance to standard chemotherapy. New approaches are required in order to identify compounds with the potential to target this tumor. OCCC are characterized by mutations in ARID1A and/or ARID1B (AT-rich interactive domain-containing proteins) that encode for members of the mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex. We have used an epigenetic library consisting of 160 compounds that targets epigenetic readers, writers, erasers, and transcriptional modulators, to screen seven OCCC cell line models (RMG1, JHOC5, OVTOKO, OVMANA, OVISE, OV207 and TOV21G) and three non-OCCC ovarian cancer cell line models (A2780, COV434 and OVCAR8). Cell lines were seeded in triplicate into 96-well plates and treated with all 160 compounds at both 5 µM and 0.5 µM, as well as with a DMSO vehicle control, for 72 hours. Following treatment, cell viability was determined using a MTS assay and each data point normalized to the DMSO control. Based on the results of viability assays, drugs were sought that preferentially targeted OCCC relative to non-OCCC cell lines. Drugs that increased cell proliferation in two or more of the OCCC lines were removed from the analysis, as were drugs that did not impact upon viability. Drug 152, ibrutinib, inhibited cell viability between 53 to 78% in 6 of the 7 OCCC cell lines at 5 µM, with an average inhibition of 64%. In non-OCCC cell lines, the average cell viability after treatment with 5 µM ibrutinib was 91% (range, 84 – 103%). Ibrutinib is a small molecule inhibitor of Bruton tyrosine kinase (BTK) that has been approved by the FDA for treatment of a number of hematological malignancies including mantle cell lymphoma, small lymphocytic lymphoma and chronic lymphocytic leukemia. BTK functions in B-cell receptor signaling, regulating B cell proliferation and survival. Ibrutinib works by irreversibly blocking the kinase activity of BTK. Interestingly, ibrutinib binding sites are also present in other tyrosine kinases, including EGFR, raising the possibility of off-target effects that can function to decrease tumor cell viability. In addition to hematological malignancies, ibrutinib is being investigated in clinical trials for the potential to impact on solid tumors including non-small cell lung cancer, certain oesophagogastric carcinoma, advanced carcinoid and pancreatic neuroendocrine tumors, squamous cell carcinoma of the head and neck, renal cell carcinoma and glioblastoma, including in some cases in combination with other therapeutic drugs including cisplatin, temozolomide and nivolumab. Following organoid drug testing, off-label use of ibrutinib in a patient with low-grade serous ovarian cancer has recently shown promising results. Research is on-going to determine the effectiveness of ibrutinib in pre-clinical models of OCCC, including analyses of the effectiveness of ibrutinib in ARID1A and ARID1B wild-type and mutant CRISPR-engineered isogenic cell line panels of OCCC. Citation Format: Yue Ma, Kristie Ann Dickson, Natisha Field, Tao Xie, Nham Tran, Deborah Joy Marsh. Epigenetic compound library screen of ovarian clear cell carcinoma cell line models identifies decreased cell viability following treatment with the Bruton tyrosine kinase inhibitor ibrutinib [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A038.
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Aulakh, Sonikpreet, Joanne Xiu, Pavel Brodskiy, Ekokobe Fonkem, Sourat Darabi, Michael J. Demeure, Soma Sengupta, et al. "Biological and prognostic relevance of epigenetic regulatory genes in high-grade gliomas (HGGs)." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 2019. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.2019.
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2019 Background: Gliomagenesis is regulated by dynamic epigenetic modifications of DNA methylation, deregulation of histones and alteration of the human Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes. These epigenetic genes are responsible for treatment resistance by inducing stemness of glioma cells and immune cells with in the tumor microenvironement (TME). We evaluated the key chromatin remodeling (CR) genes and their interactions with other regulatory genes that are of prognostic importance. Methods: 1856 HGGs underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Analyses included next-generation sequencing of DNA (592 Genes, NextSeq or WES, NovaSeq) and RNA (WTS, NovaSeq). Cell infiltration in the TME was estimated by quanTIseq. X2/Fisher’s-exact/Mann-Whitney U tests were used for comparison, and significance was determined as p-value adjusted for multiple comparison by the Benjamini-Hochberg method (q < 0.05). Overall survival (OS) was calculated from the start of temozolomide (TMZ) to last contact using insurance claims data. Results: In a cohort of 1856 HGGs, 181 (9.8%) displayed >=1 mutation of 19 CR genes considered, including mutations (mt) of histone methyltransferases (HM) comprising SETD2 (62, 3.4%), KMT2D (18, 1.0%), KMT2C (11, 0.6%); SWI/SNF complexes (SSNF) including ARID1A (32, 1.74%), ARID2 (15, 0.82%), SMARCA4 (14, 0.76%) and ARID1B (12, 0.66%); and others including ( DNMT3A, 0.94%, ASLXL1: 13, 0.98%). When compared to CR-WT, CR-mt HGGs showed higher prevalence of Tumor Mutational Burden-High (TMB-H) (23% vs. 1.3%), MSI-H/dMMR (13% vs. 0.2%), gLOH (9.5% vs 4.3%), and mts in IDH1/2 (29% vs. 14%), TP53 (55% vs. 36%), MSH6 (8.8% vs. 0.6%), and PIK3CA (18.8% vs. 8.3%) (all q<0.05). Investigation of CR-mt subgroups showed that SSNF mt had the highest MGMT-promoter methylation (68%) and IDH1/2 mt (46%), while HM and others showed similar prevalence. In IDH-WT and MSS HGGs, the CR association with TMB-H, MSH6, TP53 and PIK3CA persisted (q<0.05). When studying the immune profile, CR-mt HGGs showed significantly lower expression of immune-related genes including PD-L1 (Fold change: 0.76), PD-L2 (0.72), IDO1 (0.65), TIM3 (0.76) and CD86 (0.77) and colder TME as manifested by lower infiltrations of M2 (0.87) and higher Treg (1.27, all q<0.05); such effects were not observed in the subgroup of IDH WT/MSS tumors. Among TMZ-treated HGG tumors, CR mt was associated with improved OS (33 months vs 22m, HR: 0.713, 95% CI: 0.581-0.876, p =.001). In the IDH WT/MSS subgroup this effect was also observed (31.6m vs 19.2m, HR: 0.764, 95% CI: 0.59-0.99, p = 0.041). Conclusions: Nearly 10% of HGGs carry mts in CR genes. CR-mt HGGs possess significantly more favorable genetic alterations and colder TME compared to the CR-WT HGGs and showed better OS when treated with TMZ. Multivariate modeling and analysis of associations with specific targeted therapies is underway.
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Astier, Clémence, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque, and Sophie Postel-Vinay. "Abstract 5714: Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5714. http://dx.doi.org/10.1158/1538-7445.am2022-5714.
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Abstract Introduction: Cholangiocarcinoma (CCA) is a rare tumor accounting for less than 2% of all human malignancies. Mutations in the mammalian Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex have been identified in approximately 20% of all human cancers and more than 40% of CCA. If the role of SWI/SNF on the tumor biology and microenvironment is being uncovered in other tumor types, it remains vastly unknown in CCA. Here, we wanted to investigate, using clinical samples, the association between SWI/SNF defects, the molecular landscape and tumor immune microenvironment in CCA. Material and Methods: Mutation profiling of 103 patients with CCA from Gustave Roussy (GR) was assessed with FoundationOne® CDx 324-gene NGS panel. Formalin-fixed paraffin-embedded tumor tissues from 11 patients with CCA were analyzed for SWI/SNF (PBRM1, ARID1A, SMARCB1 and SMARCA4) and Polycomb-DUB (BAP1) subunits, as well as lymphocytic markers (CD4 and CD8). Stainings were performed using a VENTANA BenchMark ULTRA. Absolute count of positive cells per mm2 was determined by digital image analysis with the Definiens Developer XD™ by selecting at least 5 independent tumoral zones. Pairwise comparisons were performed using the Mann-Whitney test. Results: Among the patients for whom NGS data was available, the most frequently altered genes were TP53 (27%), CDKN2A (17%), KRAS (16%), ARID1A (12%), FGFR2 (12%) and PBRM1 (10%). Subunits of the SWI/SNF complex and BAP1 were mutated in 25% and 10% of cases, respectively. Tumor samples with ARID1A mutations (n=5) showed strongly decreased ARID1A expression compared to WT tumor samples (n=2) (mean = 308.03 positive nuclei (p.n)/mm2 versus 6096.82 p.n/mm2 respectively; P<0.0001) but unchanged PBRM1, SMARCB1 and SMARCA4 expression. PBRM1 mutations (n=4) were associated with decreased expression of PBRM1 (mean = 309.6 p.n/mm2 versus 4980.2 p.n/mm2 in WT samples; P<0.0001) and ARID1A (mean=1196.15 p.n/mm2; P<0.001), but unchanged SMARCB1 and SMARCA4 expression. BAP1 mutations (n=3) were also associated with decreased BAP1 and ARID1A expression (ARID1A mean = 457.70 p.n/mm2; P<0.001). ARID1A and PBRM1-altered tumor samples showed a poorly infiltrated microenvironment, with decreased CD4+ T cell (159.48 positive cells (p.c)/mm2 and 188.66 p.c/mm2 respectively versus 1126.52 p.c/mm2 for WT; P<0.0001) and CD8+ T cell density (72.38 and 76.54 p.c/mm2 versus 548.58 p.c/mm2 for WT; P<0.0001). Conclusion: Mutations in the ARID1A and PBRM1 subunits of the SWI/SNF complex are associated with a loss of protein expression. In contrast to what reported in other tumor types, ARID1A and PBRM1 mutations correlated with poorly lymphocytic TIME in CCA. Decreased PBRM1 expression is further associated with decreased ARID1A expression. Independent revalidation and further study in larger tumor series are warranted. Citation Format: Clémence Astier, Jean-Yves Scoazec, Virginie Marty, Olivia Bawa, Nicolas Signolle, Carine Ngo, Francesco Facchinetti, Antoine Hollebecque, Sophie Postel-Vinay. Characterization of SWI/SNF complex gene mutations, protein expression and tumor immune microenvironment in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5714.