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1
Hargono, Hargono, Bakti Jos, Abdullah Abdullah und Teguh Riyanto. „Inhibition Effect of Ca2+ Ions on Sucrose Hydrolysis Using Invertase“. Bulletin of Chemical Reaction Engineering & Catalysis 14, Nr. 3 (01.12.2019): 646. http://dx.doi.org/10.9767/bcrec.14.3.4437.646-653.
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Fermentable sugar for bioethanol production can be produced from molasses due to its high sucrose content but Ca2+ ions found in the molasses may affect the hydrolysis. Therefore, this paper was focused to study the effect of Ca2+ ions as CaO on sucrose hydrolysis using invertase and to obtain the kinetic parameters. The kinetic parameters (KM and Vmax) were obtained using a Lineweaver-Burk plot. The value of KM and Vmax parameters were 36.181 g/L and 21.322 g/L.h, respectively. The Ca2+ ions act as competitive inhibitor in sucrose hydrolysis using invertase. Therefore, the inhibition mechanism was followed the competitive inhibition mechanism. The value of inhibition constant was 0.833 g/g. These parameters were obtained from the non-substrate inhibition process because this study used the low substrate concentrations which means the fermentable sugar production was low. Hence, there were still more challenges to studying the simultaneous effect of substrate and Ca2+ on sucrose hydrolysis to produce high fermentable sugar. Copyright © 2019 BCREC Group. All rights reserved
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Bajaj, Anubha. „Exiguous and Scarce-SMARCB1 Deficient Medullary Renal Cell Carcinoma“. Cell & Cellular Life Sciences Journal 8, Nr. 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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Choi, Sung Kyung, Myoung Jun Kim und Jueng Soo You. „SMARCB1 Acts as a Quiescent Gatekeeper for Cell Cycle and Immune Response in Human Cells“. International Journal of Molecular Sciences 21, Nr. 11 (01.06.2020): 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.
4
Roberts, Michael, und J. Timothy Wright. „Food sugar substitutes: a brief review for dental clinicians“. Journal of Clinical Pediatric Dentistry 27, Nr. 1 (01.09.2003): 1–4. http://dx.doi.org/10.17796/jcpd.27.1.bl98u70371655hp8.
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The frequent ingestion of fermentable sugars such as sucrose, fructose, glucose and maltose is conducive to the development of caries in the teeth of susceptible individuals. Natural and artificial alternatives to these sugars have been and continue to be developed as non/low-caloric sweeteners. The US Food and Drug Administration have approved four non-caloric sweeteners at present. However, there are several other non-caloric sweeteners being commonly used in other countries.A review of these sweeteners is provided with information on a promising new agent that has not yet gained FDA approval.
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Dobrescu, Andreea Cristina, Henrique César Teixeira Veras, Cristiano Varrone und Jan Dines Knudsen. „Novel Propagation Strategy of Saccharomyces cerevisiae for Enhanced Xylose Metabolism during Fermentation on Softwood Hydrolysate“. Fermentation 7, Nr. 4 (29.11.2021): 288. http://dx.doi.org/10.3390/fermentation7040288.
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An economically viable production of second-generation bioethanol by recombinant xylose-fermenting Saccharomyces cerevisiae requires higher xylose fermentation rates and improved glucose–xylose co-consumption. Moreover, xylose-fermenting S. cerevisiae recognises xylose as a non-fermentable rather than a fermentable carbon source, which might partly explain why xylose is not fermented into ethanol as efficiently as glucose. This study proposes propagating S. cerevisiae on non-fermentable carbon sources to enhance xylose metabolism during fermentation. When compared to yeast grown on sucrose, cells propagated on a mix of ethanol and glycerol in shake flasks showed up to 50% higher xylose utilisation rate (in a defined xylose medium) and a double maximum fermentation rate, together with an improved C5/C6 co-consumption (on an industrial softwood hydrolysate). Based on these results, an automated propagation protocol was developed, using a fed-batch approach and the respiratory quotient to guide the ethanol and glycerol-containing feed. This successfully produced 71.29 ± 0.91 g/L yeast with an average productivity of 1.03 ± 0.05 g/L/h. These empirical findings provide the basis for the design of a simple, yet effective yeast production strategy to be used in the second-generation bioethanol industry for increased fermentation efficiency.
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Kakar, Smita, Xianyang Fang, Lucyna Lubkowska, Yan Ning Zhou, Gary X. Shaw, Yun-Xing Wang, Ding Jun Jin, Mikhail Kashlev und Xinhua Ji. „Allosteric Activation of Bacterial Swi2/Snf2 (Switch/Sucrose Non-fermentable) Protein RapA by RNA Polymerase“. Journal of Biological Chemistry 290, Nr. 39 (13.08.2015): 23656–69. http://dx.doi.org/10.1074/jbc.m114.618801.
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7
Roberts, Michael W., und J. Timothy Wright. „Nonnutritive, Low Caloric Substitutes for Food Sugars: Clinical Implications for Addressing the Incidence of Dental Caries and Overweight/Obesity“. International Journal of Dentistry 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/625701.
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Caries and obesity are two common conditions affecting children in the United States and other developed countries. Caries in the teeth of susceptible children have often been associated with frequent ingestion of fermentable sugars such as sucrose, fructose, glucose, and maltose. Increased calorie intake associated with sugars and carbohydrates, especially when associated with physical inactivity, has been implicated in childhood obesity. Fortunately, nonnutritive artificial alternatives and non-/low-caloric natural sugars have been developed as alternatives to fermentable sugars and have shown promise in partially addressing these health issues. Diet counseling is an important adjunct to oral health instruction. Although there are only five artificial sweeteners that have been approved as food additives by the Food and Drug Administration (FDA), there are additional five non-/low caloric sweeteners that have FDA GRAS (Generally Recognized as Safe) designation. Given the health impact of sugars and other carbohydrates, dental professionals should be aware of the nonnutritive non-/low caloric sweeteners available on the market and both their benefits and potential risks. Dental health professionals should also be proactive in helping identify patients at risk for obesity and provide counseling and referral when appropriate.
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Moelich, Nadine, Nicoline Potgieter, Francien S. Botha, James Wesley-Smith und Candice Van Wyk. „The search for a healthy sugar substitute in aid to lower the incidence of Early Childhood Caries: a comparison of sucrose, xylitol, erythritol and stevia“. South African Dental Journal 77, Nr. 08 (23.11.2022): 465–71. http://dx.doi.org/10.17159/2519-0105/2022/v77no8a2.
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A pursuit to find a healthy alternative to sucrose with less cariogenic potential, which can potentially lower the incidence of Early Childhood Caries (ECC), by means of comparison. Primary tooth enamel blocks (n=32) were randomly divided into four groups and exposed to 5% concentrations of the respective test groups (sucrose, xylitol, erythritol and stevia). All samples were inoculated with S. mutans standard strain (ATCC 25175) at room temperature. Analysis of Colony Forming Units (CFUs), acidity measurements (pH) and Scanning Electron Microscopy (SEM) observations were done after 6, 12, 18 and 24 h and compared. After 6 h, the marginal mean CFU count indicated equal S. mutans growth in all groups. Stevia showed lower CFU counts compared to other groups at 12, 18 and 24 h. The pH levels for all non-fermentable sugar substitutes (NSS) initially decreased but never below the critical pH=5.5 and stabilized from 12 to 18 h. The pH levels of sucrose dropped and remained below pH=5.5 at all time intervals. The SEM analysis of S. mutans supported the CFU results indicating growth in the presence of sucrose and reduction in the presence of the NSS.Compared to sucrose, xylitol, erythritol and stevia have less cariogenic potential with reduced growth of S. mutans and subsequent acidity levels. Stevia had the least cariogenic potential of all the NSS tested, followed by erythritol and then xylitol.
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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 und 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, Nr. 8 (12.01.2017): 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.
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Del Savio, Elisa, und Roberta Maestro. „Beyond SMARCB1 Loss: Recent Insights into the Pathobiology of Epithelioid Sarcoma“. Cells 11, Nr. 17 (24.08.2022): 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.
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Liu, Hongyu, Yang Zhao, Guizhen Zhao, Yongjie Deng, Y. Eugene Chen und Jifeng Zhang. „SWI/SNF Complex in Vascular Smooth Muscle Cells and Its Implications in Cardiovascular Pathologies“. Cells 13, Nr. 2 (16.01.2024): 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.
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Wanior, Marek, Andreas Krämer, Stefan Knapp und Andreas C. Joerger. „Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy“. Oncogene 40, Nr. 21 (03.05.2021): 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.
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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 und 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, Nr. 13 (06.07.2023): 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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Moreira, B. R. A., R. S. Viana, L. A. M. Lisboa, P. R. M. Lopes, P. A. M. Figueiredo, S. B. Ramos, C. S. B. Bonini, V. D. R. Trindade, M. G. O. Andrade und A. May. „Jasmonic Acid and K-Phosphite Enhance Productivity and Technological Quality of Sugarcane Crop“. Journal of Agricultural Science 11, Nr. 14 (31.08.2019): 254. http://dx.doi.org/10.5539/jas.v11n14p254.
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Plant resistance inducers are cost-effective and environmentally pleasing strategies of plant protection to mitigate biotic and abiotic agents threatening food safety and energy security. We, accordingly, present jasmonic acid and k-phosphite as low-cost strategies to enhance productive yield and technological quality of sugarcane crop. Exogenously treatment of the sugarcane variety ‘SP81-3250’ consisted of carrying out foliar application of jasmonic acid at 1, 1.5 and 2 ml L-1 and K-phosphite at 2, 4 and 6 ml L-1 before crop flowering. Interestingly, both systemic phytorregulator and foliar fertilizer at the lowest doses significantly improved contents of total soluble solids and sucrose, as well as productive yield of fermentable sugars. Jasmonic acid could promote growth and development by triggering either non-enzymatic or enzymatic mechanisms in the host self-defense system to support of external stresses, including herbivory by sugarcane-borer. K-phosphite could improve crop performance by not only releasing water-soluble inorganic ions like phosphorus and potash, but also by signaling synthesis of phytoalexins. Purity of cane juice and productivity of stalks sharply decreased, as the doses of the plant-resistance inducers increased. Jasmonic acid and k-phosphite at unbalanced endogenous levels could inhibit physiological ripening and specific enzymatical activity of alkaline invertases and sucrose-phosphate synthase, thereby influencing bioavailability of sucrose. The lower the sucrose content, the poorer the technological quality of sugarcane crop. The conclusion is, therefore, jasmonic acid and K-phosphite at lower doses prove to be effective induced resistance techniques to produce richer feedstock, with potential to produce ethanol fuel and refined sugar in sugar-energy plants.
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Collingwood, TN, FD Urnov und AP Wolffe. „Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription“. Journal of Molecular Endocrinology 23, Nr. 3 (01.12.1999): 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.
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Parfenov, Asfold I. „The value of increased intestinal permeability in the pathogenesis of internal diseases“. Terapevticheskii arkhiv 96, Nr. 2 (30.03.2024): 85–90. http://dx.doi.org/10.26442/00403660.2024.02.202587.
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In the process of evolution in the gastrointestinal tract, a system of protection against bacterial and food antigens from getting into the blood was formed. The causes of increased intestinal permeability (IIP) can be microbiota imbalance, use of antibiotics, non-steroidal anti-inflammatory drugs, stress, diet rich in fructose, glucose, sucrose and long-chain fatty acids. The appearance of IIP may be of paramount importance in the pathogenesis of autoimmune diseases. A diet low in fermentable oligodimonosaccharides and polyols, pre- and probiotics, polyphenols, vitamins, short-chain fatty acids, dietary fiber, glutamine contributes to the reduction of IIP. It has been established that the cytoprotector rebamipide strengthens the barrier function throughout the gastrointestinal tract, which is reflected in practical recommendations for its use in diseases accompanied by IIP. The study of this direction will contribute to the emergence of a new strategy for the treatment of internal diseases.
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Cruz-Tapia, Roberto Onner, Ana María Cano-Valdez, Abelardo Meneses-García, Lorena Correa-Arzate, Adriana Molotla-Fragoso, Guillermo Villagómez-Olea, Diana Brisa Sevilla-Lizcano und 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, Nr. 11 (30.10.2024): 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.
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Ngo, Carine, und Sophie Postel-Vinay. „Immunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments“. Biomedicines 10, Nr. 3 (11.03.2022): 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.
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Padilla-Benavides, Teresita, Pablo Reyes-Gutierrez und Anthony N. Imbalzano. „Regulation of the Mammalian SWI/SNF Family of Chromatin Remodeling Enzymes by Phosphorylation during Myogenesis“. Biology 9, Nr. 7 (03.07.2020): 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.
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Hasan, Nesrin, und Nita Ahuja. „The Emerging Roles of ATP-Dependent Chromatin Remodeling Complexes in Pancreatic Cancer“. Cancers 11, Nr. 12 (25.11.2019): 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.
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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, Nr. 5 (Mai 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.
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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, Nr. 3 (01.02.2020): 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.
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Hu, Xiaolong, Mengjie Li, Xue Hao, Yi Lu, Lei Zhang und 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, Nr. 3 (04.03.2021): 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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Li, Jing Jing, und Cheok Soon Lee. „The Role of the AT-Rich Interaction Domain 1A Gene (ARID1A) in Human Carcinogenesis“. Genes 15, Nr. 1 (19.12.2023): 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.
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Salli, Krista, Markus J. Lehtinen, Kirsti Tiihonen und Arthur C. Ouwehand. „Xylitol’s Health Benefits beyond Dental Health: A Comprehensive Review“. Nutrients 11, Nr. 8 (06.08.2019): 1813. http://dx.doi.org/10.3390/nu11081813.
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Xylitol has been widely documented to have dental health benefits, such as reducing the risk for dental caries. Here we report on other health benefits that have been investigated for xylitol. In skin, xylitol has been reported to improve barrier function and suppress the growth of potential skin pathogens. As a non-digestible carbohydrate, xylitol enters the colon where it is fermented by members of the colonic microbiota; species of the genus Anaerostipes have been reported to ferment xylitol and produce butyrate. The most common Lactobacillus and Bifidobacterium species do not appear to be able to grow on xylitol. The non-digestible but fermentable nature of xylitol also contributes to a constipation relieving effect and improved bone mineral density. Xylitol also modulates the immune system, which, together with its antimicrobial activity contribute to a reduced respiratory tract infection, sinusitis, and otitis media risk. As a low caloric sweetener, xylitol may contribute to weight management. It has been suggested that xylitol also increases satiety, but these results are not convincing yet. The benefit of xylitol on metabolic health, in addition to the benefit of the mere replacement of sucrose, remains to be determined in humans. Additional health benefits of xylitol have thus been reported and indicate further opportunities but need to be confirmed in human studies.
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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, Nr. 7893 (22.12.2021): 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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El Hadidy und Uversky. „Intrinsic Disorder of the BAF Complex: Roles in Chromatin Remodeling and Disease Development“. International Journal of Molecular Sciences 20, Nr. 21 (23.10.2019): 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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Reske, Jake J., Mike R. Wilson, Jeanne Holladay, Marc Wegener, Marie Adams und Ronald L. Chandler. „SWI/SNF inactivation in the endometrial epithelium leads to loss of epithelial integrity“. Human Molecular Genetics 29, Nr. 20 (15.10.2020): 3412–30. http://dx.doi.org/10.1093/hmg/ddaa227.
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Abstract Although ARID1A mutations are a hallmark feature, mutations in other SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling subunits are also observed in endometrial neoplasms. Here, we interrogated the roles of Brahma/SWI2-related gene 1 (BRG1, SMARCA4), the SWI/SNF catalytic subunit, in the endometrial epithelium. BRG1 loss affects more than one-third of all active genes and highly overlaps with the ARID1A gene regulatory network. Chromatin immunoprecipitation studies revealed widespread subunit-specific differences in transcriptional regulation, as BRG1 promoter interactions are associated with gene activation, while ARID1A binding is associated with gene repression. However, we identified a physiologically relevant subset of BRG1 and ARID1A co-regulated epithelial identity genes. Mice were genetically engineered to inactivate BRG1 specifically in the endometrial epithelium. Endometrial glands were observed embedded in uterine myometrium, indicating adenomyosis-like phenotypes. Molecular similarities were observed between BRG1 and ARID1A mutant endometrial cells in vivo, including loss of epithelial cell adhesion and junction genes. Collectively, these studies illustrate overlapping contributions of multiple SWI/SNF subunit mutations in the translocation of endometrium to distal sites, with loss of cell integrity being a common feature in SWI/SNF mutant endometrial epithelia.
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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, Nr. 7 (21.07.2023): 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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Mat Ali, N. N., F. I. Abu Bakar, M. F. Abu Bakar, N. H. Malik, N. Muhammad, S. F. Sabran, F. Pa'ee et al. „The effect of soursop as fermentable substrate in formulating flavoured water kefir beverage“. Food Research 8, Supplementary 5 (23.09.2024): 20–25. http://dx.doi.org/10.26656/fr.2017.8(s5).4.
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Water kefir is a fermented sucrose solution from fruits or vegetable juices that produces acidic fermented beverages. This study aimed to explore the usage of soursop pulp as a fermentable substrate to formulate a non-dairy fermented beverage. In this study, fruit juice from soursop was fermented with water kefir grains for 48 hrs at 24°C. The first fermentation of sugary water with water kefir grains was carried out for four days and the second fermentation of the fermented water with soursop juice was carried out for two days at room temperature. The beverage formulations based on soursop concentrations were 25, 50, 75 and 100% (v/v). Results showed that the physicochemical analyses were in the range of (pH = 3.22 to 3.34, total soluble solid (TSS) = 4.59 to 10.42°Bx, and colour with lightness (L*) of 31.17 to 56.29, red and green intensity (a*) of -0.98 to -2.76 and yellow and blue intensity (b*) of -3.06 to 2.75). The alcohol content ranged from 0.43 to 0.62%. The total phenolic content decreased significantly (p<0.05) over time for each sample. Due to the process, it had heavily influenced the panellists during the sensory tests, in which favoured sample with 50% v/v soursop in the water kefir beverage. In conclusion, the utilization of soursop juice in the production of water kefir beverages can be introduced as a newly flavoured fermented drink using water kefir grains.
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Lu, Ping, Si-Yu Dai, Ling-Tao Yong, Bai-Hui Zhou, Nan Wang, Yuan-Yuan Dong, Wei-Can Liu, Fa-Wei Wang, Hao-Yu Yang und Xiao-Wei Li. „A Soybean Sucrose Non-Fermenting Protein Kinase 1 Gene, GmSNF1, Positively Regulates Plant Response to Salt and Salt–Alkali Stress in Transgenic Plants“. International Journal of Molecular Sciences 24, Nr. 15 (05.08.2023): 12482. http://dx.doi.org/10.3390/ijms241512482.
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Soybean is one of the most widely grown oilseed crops worldwide. Several unfavorable factors, including salt and salt–alkali stress caused by soil salinization, affect soybean yield and quality. Therefore, exploring the molecular basis of salt tolerance in plants and developing genetic resources for genetic breeding is important. Sucrose non-fermentable protein kinase 1 (SnRK1) belongs to a class of Ser/Thr protein kinases that are evolutionarily highly conserved direct homologs of yeast SNF1 and animal AMPKs and are involved in various abiotic stresses in plants. The GmPKS4 gene was experimentally shown to be involved with salinity tolerance. First, using the yeast two-hybrid technique and bimolecular fluorescence complementation (BiFC) technique, the GmSNF1 protein was shown to interact with the GmPKS4 protein. Second, the GmSNF1 gene responded positively to salt and salt–alkali stress according to qRT-PCR analysis, and the GmSNF1 protein was localized in the nucleus and cytoplasm using subcellular localization assay. The GmSNF1 gene was then heterologously expressed in yeast, and the GmSNF1 gene was tentatively identified as having salt and salt–alkali tolerance function. Finally, the salt–alkali tolerance function of the GmSNF1 gene was demonstrated by transgenic Arabidopsis thaliana, soybean hairy root complex plants overexpressing GmSNF1 and GmSNF1 gene-silenced soybean using VIGS. These results indicated that GmSNF1 might be useful in genetic engineering to improve plant salt and salt–alkali tolerance.
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Crodian, Jennifer S., Bethany M. Weldon, Yu-Chun Tseng, Birgit Cabot und 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, Nr. 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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Keim, Juan P., Mónica Gandarillas, Daniel Benavides, Jaime Cabanilla, Rubén G. Pulido, Oscar A. Balocchi und Annick Bertrand. „Nutrient concentrations and profile of non-structural carbohydrates vary among different Brassica forages“. Animal Production Science 60, Nr. 12 (2020): 1503. http://dx.doi.org/10.1071/an19472.
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Context Brassica forages are used in times of seasonal shortage to fulfil nutritional requirements of beef cattle, dairy cows, sheep or pigs. Although brassicas have been reported with high concentrations of readily fermentable carbohydrate, details have not been fully described and there is little information about the non-structural carbohydrate (NSC) profiles of Brassica forages. Aim The study was designed to evaluate nutrient concentrations, as well as NSC levels and constituents, of the main Brassica forages and to determine differences among varieties. Methods Five varieties of each of the four main forage brassicas (summer turnip, forage rape, kale and swede) were grown in plots and harvested for chemical analysis of the nutrient concentrations and NSC profiles of leaf and bulb (turnip and swede) and leaf and stem (rape and kale) components. Key results Brassica species differed in the amounts and types of NSC; swede had the highest concentration of NSC, mainly comprising sugars (glucose and fructose), followed by kale (with similar proportions of glucose, sucrose and fructose), turnip (with similar concentrations of glucose and starch and slightly lower fructose), and forage rape (in which starch was the main NSC). Forage chemical composition and NSC profile of plant organs varied among varieties of individual Brassica forages; for example, there were significant differences among swede varieties for concentrations of starch and sugar (total and profile) in bulbs. Conclusions Brassica forages differed with respect to quantities and types of NSC; swede had higher concentrations, mainly composed of glucose and fructose, followed by kale with similar proportions of glucose, sucrose and fructose, and turnip with NSC represented by glucose, starch and slightly lower fructose; and finally, forage rape, in which starch was the main NSC. Chemical composition, as well as NSC profile of plant organs (leaves, bulbs or stems), varied among varieties of Brassica species. Implications The approach described here has implications for ration formulation and is useful when considering the nutritional and dietary requirements of the animals of interest, because the type of Brassica, the variety and the proportion of plant organs can affect animal performance.
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Angelico, Giuseppe, Giulio Attanasio, Lorenzo Colarossi, Cristina Colarossi, Matteo Montalbano, Eleonora Aiello, Federica Di Vendra, Marzia Mare, Nicolas Orsi und Lorenzo Memeo. „ARID1A Mutations in Gastric Cancer: A Review with Focus on Clinicopathological Features, Molecular Background and Diagnostic Interpretation“. Cancers 16, Nr. 11 (30.05.2024): 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, Nr. 17 (03.09.2024): 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.
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Roth, Bodil, Mohamed Nseir, Håkan Jeppsson, Mauro D’Amato, Kristina Sundquist und Bodil Ohlsson. „A Starch- and Sucrose-Reduced Diet Has Similar Efficiency as Low FODMAP in IBS—A Randomized Non-Inferiority Study“. Nutrients 16, Nr. 17 (09.09.2024): 3039. http://dx.doi.org/10.3390/nu16173039.
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A diet with low content of fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) is established treatment for irritable bowel syndrome (IBS), with well-documented efficiency. A starch- and sucrose-reduced diet (SSRD) has shown similar promising effects. The primary aim of this randomized, non-inferiority study was to test SSRD against low FODMAP and compare the responder rates (RR = ∆Total IBS-SSS ≥ −50) to a 4-week dietary intervention of either diet. Secondary aims were to estimate responders of ≥100 score and 50% reduction; effects on extraintestinal symptoms; saturation; sugar craving; anthropometric parameters; and blood pressure. 155 IBS patients were randomized to SSRD (n = 77) or low FODMAP (n = 78) for 4 weeks, with a follow-up 5 months later without food restrictions. The questionnaires Rome IV, IBS-severity scoring system (IBS-SSS), and visual analog scale for IBS (VAS-IBS) were completed at baseline and after 2 and 4 weeks and 6 months. Weight, height, waist circumference, and blood pressures were measured. Comparisons were made within the groups and between changes in the two groups. There were no differences between groups at baseline. The responder rate of SSRD was non-inferior compared with low FODMAPs at week 2 (79.2% vs. 73.1%; p = 0.661;95% confidence interval (CI) = −20–7.2) and week 4 (79.2% vs. 78.2%; p = 1.000;95%CI = −14–12). Responder rate was still high when defined stricter. All gastrointestinal and extraintestinal symptoms were equally improved (p < 0.001 in most variables). SSRD rendered greater reductions in weight (p = 0.006), body mass index (BMI) (p = 0.005), and sugar craving (p = 0.05), whereas waist circumference and blood pressure were equally decreased. Weight and BMI were regained at follow-up. In the SSRD group, responders at 6 months still had lowered weight (−0.7 (−2.5–0.1) vs. 0.2 (−0.7–2.2) kg; p = 0.005) and BMI (−0.25 (−0.85–0.03) vs. 0.07 (−0.35–0.77) kg/m2; p = 0.009) compared with baseline in contrast to non-responders. Those who had tested both diets preferred SSRD (p = 0.032). In conclusion, a 4-week SSRD intervention was non-inferior to low FODMAP regarding responder rates of gastrointestinal IBS symptoms. Furthermore, strong reductions of extraintestinal symptoms were found in both groups, whereas reductions in weight, BMI, and sugar craving were most pronounced following SSRD.
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Ahadi, Mahsa S., Talia L. Fuchs, Adele Clarkson, Amy Sheen, Loretta Sioson, Angela Chou und Anthony J. Gill. „Switch/sucrose‐non‐fermentable ( SWI / SNF ) complex ( SMARCA4 , SMARCA2 , INI1 / SMARCB1 )‐deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas“. Histopathology 80, Nr. 6 (24.02.2022): 906–21. http://dx.doi.org/10.1111/his.14612.
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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, Nr. 12 (10.12.2020): 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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Chinnaiyan, Arul M. „Abstract IA021: Targeting epigenetic regulators of oncogenic transcription factors“. Cancer Research 82, Nr. 23_Supplement_2 (01.12.2022): 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 und Xiaoling Deng. „MiR-199a-5p-Regulated SMARCA4 Promotes Oral Squamous Cell Carcinoma Tumorigenesis“. International Journal of Molecular Sciences 24, Nr. 5 (01.03.2023): 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, Nr. 7 (18.09.2018): 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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Stacchiotti, Silvia, und Brian Andrew Van Tine. „Synovial Sarcoma: Current Concepts and Future Perspectives“. Journal of Clinical Oncology 36, Nr. 2 (10.01.2018): 180–87. http://dx.doi.org/10.1200/jco.2017.75.1941.
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Synovial sarcoma (SS) is a rare sarcoma driven by a translocation between SS18 and SSX 1, 2, or 4. With approximately 800 to 1,000 cases a year in the United States, it most commonly affects young adults between the ages of 15 and 30 years. The resultant tumors are either monophasic (pure sarcomas), biphasic (a combination or epithelioid and sarcomatous components), or poorly differentiated. The hybrid transcription factor SS18:SSX alters SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling and global methylation patterns that may allow for future therapeutic opportunities. In this review, we focus on the pharmacologic management of SS, both in the curative setting, where the standard approach is wide surgical excision combined with radiotherapy and/or (neo)adjuvant chemotherapy as appropriate, and in the palliative setting. In advanced disease, chemotherapy with anthracyclines and/or ifosfamide, trabectedin, or pazopanib has been demonstrated to be more active compared with other soft tissue sarcomas. In addition, a better understanding of the molecular and immunologic characteristics of SS has allowed for the identification of new potential targets and the development of novel biology-driven therapies that are all at different stages of testing. There include targeted agents, immunotherapy, and metabolic therapies. Because the impact of these strategies for improving SS outcome is still limited, current and future research is strongly needed to better understand the tumor biology, to identify predictive biomarkers, and to improve the outcomes for patients with SS.
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Damaceno, Jéssica de Medeiros, Larissa de Oliveira Bispo, Cristiane De Carli, Lucas Vinícius Cavichi, Carla Adriana Pizarro Schmidt, Valdemar Padilha Feltrin, Aziza Kamal Genena und Celeide Pereira. „Symbiotic profile of petit suisse diet cheese with added brazilian nuts extract, Bifidobacterium bifidum and Lactobacillus paracasei“. OBSERVATÓRIO DE LA ECONOMÍA LATINOAMERICANA 22, Nr. 1 (10.01.2024): 284–96. http://dx.doi.org/10.55905/oelv22n1-016.
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Functional foods, which promise to help cure or prevent diseases, are the new trend in the powerful food market at the beginning of the 21st century. Probiotics are live microorganisms that can be added as supplements in the diet, beneficially affecting the development of the microbial flora in the gut. Prebiotics, on the other hand, are non-digestible but fermentable oligosaccharides whose function is to change the activity and composition of the intestinal microbiota with the perspective of promoting the health of the host. The Brazil nut is an oilseed, its lipid content is of good quality, with high levels of unsaturated fatty acids, components of vitamins B1, B2, B3 and selenium that have antioxidant potential. Currently, the consumption of low-calorie foods and sweeteners has increased a lot in recent years and the dairy industry, in an attempt to cater this public, has been introducing low-calorie dairy derivatives into the market, the so-called “light” and “diet” products, which use various types of sweeteners as substitutes for sucrose. Petit Suisse cheese is a cheese made with skimmed milk and cream, with very high humidity, light consistency, smooth, creamy and can have a sweet or salty flavor. The objective of this work was to produce formulations of Petit Suisse cheese added with acidifying bacteria, probiotic bacteria Bifidobacterium bifidum and Lactobacillus paracasei, Brazil nut extract, sweeteners and to verify the symbiotic potential during storage.
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Leng, Lingying, Lin Yang, Wenbin Tu, Rohan Rej, Srinivasa Rao Allu, Liyue Huang, Wei Jiang et al. „Abstract 4506: Discovery of potent, highly selective and orally efficacious SMARCA2 degraders“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 4506. http://dx.doi.org/10.1158/1538-7445.am2024-4506.
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Abstract In human non-small cell lung cancer, melanoma and other types of human cancers, the mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated, which leads to inactivation of its functions. SMARCA2, a close homologous protein of SMARCA4, is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the discovery and biological evaluation of potent, highly selective, orally efficacious SMARCA2 PROTAC degraders exemplified by UM-SMD-8801. UM-SMD-8801 has DC50 <10 nM and Dmax >90% against SMARCA2 and >1,000-fold degradation selectivity over SMARCA4. Consistently, UM-SMD-8801 potently inhibits cell growth in SMARCA4 mutated cancer cell lines with low nanomolar IC50 values and shows >100-fold weaker activity in SMARCA4 wild-type cancer cell lines. UM-SMD-8801 has a good overall pharmacokinetic profile and an excellent oral bioavailability in mice. Oral administration of UM-SMD-8801 is highly effective in reducing SMARCA2 protein by >90% in tumor tissues in mice, while having minimal effect on SMARCA4 protein. UM-SMD-8801 represents a very promising SMARCA2 degrader for extensive evaluation as a potential new therapy for the treatment of SMARCA4-deficient human cancers. Citation Format: Lingying Leng, Lin Yang, Wenbin Tu, Rohan Rej, Srinivasa Rao Allu, Liyue Huang, Wei Jiang, Yu Wang, Jeanne Stuckey, Farzad R Sarkari, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of potent, highly selective and orally efficacious SMARCA2 degraders [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 4506.
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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, Nr. 1 (13.03.2008): 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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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, Nr. 1_Supplement (01.05.2022): 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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Krishnamurthy, Nithya, Shumei Kato, Scott Lippman und Razelle Kurzrock. „Chromatin remodeling (SWI/SNF) complexes, cancer, and response to immunotherapy“. Journal for ImmunoTherapy of Cancer 10, Nr. 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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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, Nr. 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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Van Rechem, Capucine. „EPCO-43. CHROMATIN REMODELERS LOST IN TRANSLATION“. Neuro-Oncology 24, Supplement_7 (01.11.2022): 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 (01.06.2023): 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.