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1
Dorna, Dawid, and Jarosław Paluszczak. "The Emerging Significance of Histone Lysine Demethylases as Prognostic Markers and Therapeutic Targets in Head and Neck Cancers." Cells 11, no. 6 (March 17, 2022): 1023. http://dx.doi.org/10.3390/cells11061023.
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Epigenetic aberrations, associated with altered DNA methylation profiles and global changes in the level of histone modifications, are commonly detected in head and neck squamous cell carcinomas (HNSCC). Recently, histone lysine demethylases have been implicated in the pathogenesis of HNSCC and emerged as potential molecular targets. Histone lysine demethylases (KDMs) catalyze the removal of methyl groups from lysine residues in histones. By affecting the methylation of H3K4, H3K9, H3K27, or H3K36, these enzymes take part in transcriptional regulation, which may result in changes in the level of expression of tumor suppressor genes and protooncogenes. KDMs are involved in many biological processes, including cell cycle control, senescence, DNA damage response, and heterochromatin formation. They are also important regulators of pluripotency. The overexpression of most KDMs has been observed in HNSCC, and their inhibition affects cell proliferation, apoptosis, cell motility, invasiveness, and stemness. Of all KDMs, KDM1, KDM4, KDM5, and KDM6 proteins are currently regarded as the most promising prognostic and therapeutic targets in head and neck cancers. The aim of this review is to present up-to-date knowledge on the significance of histone lysine demethylases in head and neck carcinogenesis and to discuss the possibility of using them as prognostic markers and pharmacological targets in patients’ treatment.
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Vicioso-Mantis, Marta, Samuel Aguirre, and Marian A. Martínez-Balbás. "JmjC Family of Histone Demethylases Form Nuclear Condensates." International Journal of Molecular Sciences 23, no. 14 (July 11, 2022): 7664. http://dx.doi.org/10.3390/ijms23147664.
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The Jumonji-C (JmjC) family of lysine demethylases (KDMs) (JMJC-KDMs) plays an essential role in controlling gene expression and chromatin structure. In most cases, their function has been attributed to the demethylase activity. However, accumulating evidence demonstrates that these proteins play roles distinct from histone demethylation. This raises the possibility that they might share domains that contribute to their functional outcome. Here, we show that the JMJC-KDMs contain low-complexity domains and intrinsically disordered regions (IDR), which in some cases reached 70% of the protein. Our data revealed that plant homeodomain finger protein (PHF2), KDM2A, and KDM4B cluster by phase separation. Moreover, our molecular analysis implies that PHF2 IDR contributes to transcription regulation. These data suggest that clustering via phase separation is a common feature that JMJC-KDMs utilize to facilitate their functional responses. Our study uncovers a novel potential function for the JMJC-KDM family that sheds light on the mechanisms to achieve the competent concentration of molecules in time and space within the cell nucleus.
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Wigle, Tim J., Kerren K. Swinger, John E. Campbell, Michael D. Scholle, John Sherrill, Elizabeth A. Admirand, P. Ann Boriack-Sjodin, et al. "A High-Throughput Mass Spectrometry Assay Coupled with Redox Activity Testing Reduces Artifacts and False Positives in Lysine Demethylase Screening." Journal of Biomolecular Screening 20, no. 6 (March 9, 2015): 810–20. http://dx.doi.org/10.1177/1087057115575689.
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Demethylation of histones by lysine demethylases (KDMs) plays a critical role in controlling gene transcription. Aberrant demethylation may play a causal role in diseases such as cancer. Despite the biological significance of these enzymes, there are limited assay technologies for study of KDMs and few quality chemical probes available to interrogate their biology. In this report, we demonstrate the utility of self-assembled monolayer desorption/ionization (SAMDI) mass spectrometry for the investigation of quantitative KDM enzyme kinetics and for high-throughput screening for KDM inhibitors. SAMDI can be performed in 384-well format and rapidly allows reaction components to be purified prior to injection into a mass spectrometer, without a throughput-limiting liquid chromatography step. We developed sensitive and robust assays for KDM1A (LSD1, AOF2) and KDM4C (JMJD2C, GASC1) and screened 13,824 compounds against each enzyme. Hits were rapidly triaged using a redox assay to identify compounds that interfered with the catalytic oxidation chemistry used by the KDMs for the demethylation reaction. We find that overall this high-throughput mass spectrometry platform coupled with the elimination of redox active compounds leads to a hit rate that is manageable for follow-up work.
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Bonnici, Joanna, Anthony Tumber, Akane Kawamura, and Christopher J. Schofield. "Inhibitors of both the N -methyl lysyl- and arginyl-demethylase activities of the JmjC oxygenases." Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1748 (April 23, 2018): 20170071. http://dx.doi.org/10.1098/rstb.2017.0071.
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The Jumonji C (JmjC) family of 2-oxoglutarate (2OG)-dependent oxygenases have established roles in the regulation of transcription via the catalysis of demethylation of N ε - methylated lysine residues in histone tails, especially the N - terminal tail of histone H3. Most human JmjC N ɛ -methyl lysine demethylases (KDMs) are complex enzymes, with ‘reader domains’ in addition to their catalytic domains. Recent biochemical evidence has shown that some, but not all, JmjC KDMs also have N ω - methyl arginyl demethylase (RDM) activity. JmjC KDM activity has been linked to multiple cancers and some JmjC proteins are therapeutic targets. It is, therefore, important to test not only whether compounds in development inhibit the KDM activity of targeted JmjC demethylases, but also whether they inhibit other activities of these proteins. Here we report biochemical studies on the potential dual inhibition of JmjC KDM and RDM activities using a model JmjC demethylase, KDM4E (JMJD2E). The results reveal that all of the tested compounds inhibit both the KDM and RDM activities, raising questions about the in vivo effects of the inhibitors. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
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Kim, Yoon-Jung, Dong Hoon Lee, Yong-Sung Choi, Jin-Hyun Jeong, and So Hee Kwon. "Benzo[b]tellurophenes as a Potential Histone H3 Lysine 9 Demethylase (KDM4) Inhibitor." International Journal of Molecular Sciences 20, no. 23 (November 25, 2019): 5908. http://dx.doi.org/10.3390/ijms20235908.
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Gene expression and tumor growth can be regulated by methylation levels of lysine residues on histones, which are controlled by histone lysine demethylases (KDMs). Series of benzo[b]tellurophene and benzo[b]selenophene compounds were designed and synthesized and they were evaluated for histone H3 lysine 9 demethylase (KDM4) inhibitory activity. Among the carbamates, alcohol and aromatic derivatives, tert-butyl benzo[b]tellurophen-2-ylmethylcarbamate (compound 1c) revealed KDM4 specific inhibitory activity in cervical cancer HeLa cells, whereas the corresponding selenium or oxygen substitute compounds did not display any inhibitory activity toward KDM4. Compound 1c also induced cell death in cervical and colon cancer but not in normal cells. Thus, compound 1c, a novel inhibitor of KDM4, constitutes a potential therapeutic and research tool against cancer.
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Guo, Xiaoqiang, and Qiaoxia Zhang. "The emerging role of histone demethylases in renal cell carcinoma." Journal of Kidney Cancer and VHL 4, no. 2 (May 2, 2017): 1–5. http://dx.doi.org/10.15586/jkcvhl.2017.56.
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Renal cell carcinoma (RCC), the most common kidney cancer, is responsible for more than 100,000 deaths per year worldwide. The molecular mechanism of RCC is poorly understood. Many studies have indicated that epigenetic changes such as DNA methylation, noncoding RNAs, and histone modifications are central to the pathogenesis of cancer. Histone demethylases (KDMs) play a central role in histone modifications. There is emerging evidence that KDMs such as KDM3A, KDM5C, KDM6A, and KDM6B play important roles in RCC. The available literature suggests that KDMs could promote RCC development and progression via hypoxia-mediated angiogenesis pathways. Small-molecule inhibitors of KDMs are being developed and used in preclinical studies; however, their clinical relevance is yet to be established. In this mini review, we summarize our current knowledge on the putative role of histone demethylases in RCC.
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Wang, Zhanxin, and Dinshaw J. Patel. "Small molecule epigenetic inhibitors targeted to histone lysine methyltransferases and demethylases." Quarterly Reviews of Biophysics 46, no. 4 (September 2, 2013): 349–73. http://dx.doi.org/10.1017/s0033583513000085.
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AbstractAltered chromatin structures and dynamics are responsible for a range of human malignancies, among which the status of histone lysine methylation remains of paramount importance. Histone lysine methylation is maintained by the relative activities of sequence-specific methyltransferase (KMT) writers and demethylase (KDM) erasers, with aberrant enzymatic activities or expression profiles closely correlated with multiple human diseases. Hence, targeting these epigenetic enzymes should provide a promising avenue for pharmacological intervention of aberrantly marked sites within the epigenome. Here we present an up-to-date critical evaluation on the development and optimization of potent small molecule inhibitors targeted to histone KMTs and KDMs, with the emphasis on contributions of structural biology to development of epigenetic drugs for therapeutic intervention. We anticipate that ongoing advances in the development of epigenetic inhibitors should lead to novel drugs that site-specifically target KMTs and KDMs, key enzymes responsible for maintenance of the lysine methylation landscape in the epigenome.
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Nic-Can, Geovanny I., Beatriz A. Rodas-Junco, Leydi M. Carrillo-Cocom, Alejandro Zepeda-Pedreguera, Ricardo Peñaloza-Cuevas, Fernando J. Aguilar-Ayala, and Rafael A. Rojas-Herrera. "Epigenetic Regulation of Adipogenic Differentiation by Histone Lysine Demethylation." International Journal of Molecular Sciences 20, no. 16 (August 12, 2019): 3918. http://dx.doi.org/10.3390/ijms20163918.
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Obesity is a rising public health problem that contributes to the development of several metabolic diseases and cancer. Adipocyte precursors outside of adipose depots that expand due to overweight and obesity may have a negative impact on human health. Determining how progenitor cells acquire a preadipocyte commitment and become mature adipocytes remains a significant challenge. Over the past several years, we have learned that the establishment of cellular identity is widely influenced by changes in histone marks, which in turn modulate chromatin structure. In this regard, histone lysine demethylases (KDMs) are now emerging as key players that shape chromatin through their ability to demethylate almost all major histone methylation sites. Recent research has shown that KDMs orchestrate the chromatin landscape, which mediates the activation of adipocyte-specific genes. In addition, KDMs have functions in addition to their enzymatic activity, which are beginning to be revealed, and their dysregulation seems to be related to the development of metabolic disorders. In this review, we highlight the biological functions of KDMs that contribute to the establishment of a permissive or repressive chromatin environment during the mesenchymal stem cell transition into adipocytes. Understanding how KDMs regulate adipogenesis might prompt the development of new strategies for fighting obesity-related diseases.
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Nanduri, Jayasri, Ning Wang, Benjamin L. Wang, and Nanduri R. Prabhakar. "Lysine demethylase KDM6B regulates HIF-1α-mediated systemic and cellular responses to intermittent hypoxia." Physiological Genomics 53, no. 9 (September 1, 2021): 385–94. http://dx.doi.org/10.1152/physiolgenomics.00045.2021.
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Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA). Rodents treated with IH exhibit hypertension. Hypoxia-inducible factor (HIF)-1-dependent transcriptional activation of NADPH oxidases ( Nox) and the resulting increase in reactive oxygen species (ROS) levels is a major molecular mechanism underlying IH/OSA-induced hypertension. Jumanji C (JmjC)-containing histone lysine demethylases (JmjC-KDMs) are coactivators of HIF-1-dependent transcriptional activation. In the present study, we tested the hypothesis that JmjC-KDMs are required for IH-evoked HIF-1 transcriptional activation of Nox4 and the ensuing hypertension. Studies were performed on pheochromocytoma (PC)12 cells and rats. IH increased KDM6B protein and enzyme activity in PC12 cells in an HIF-1-independent manner as evidenced by unaltered KDM6B activation by IH in HIF-1α shRNA-treated cells. Cells treated with IH showed increased HIF-1-dependent Nox4 transcription as indicated by increased HIF-1α binding to hypoxia-responsive element (HRE) sequence of the Nox4 gene promoter demonstrated by chromatin immunoprecipitation (ChiP) assay. Pharmacological blockade of KDM6B with GSKJ4, a specific KDM6 inhibitor, or genetic silencing of KDM6B with shRNA abolished IH-induced Nox4 transcriptional activation by blocking HIF-1α binding to the promoter of the Nox4 gene. Treating IH-exposed rats with GSKJ4 showed: 1) absence of KDM6B activation and HIF-1-dependent Nox4 transcription in the adrenal medullae, and 2) absence of elevated plasma catecholamines and hypertension. Collectively, these findings indicate that KDM6B functions as a coactivator of HIF-1-mediated Nox4 transactivation and demonstrates a hitherto uncharacterized role for KDMs in IH-induced hypertension by HIF-1.
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Karásek, Matej, and Ľubica Kollárová. "The Christian Democratic Youth of Slovakia: Christian Legacy, Post-Socialist Memory and the Present Spirit of Capitalism." Ethnologia Actualis 15, no. 1 (June 1, 2015): 40–64. http://dx.doi.org/10.1515/eas-2015-0008.
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Abstract The subject of this case study is the youth political organisation Christian Democratic Youth of Slovakia (KDMS). The first parts of this paper are dedicated to history and the structure of organisation. Latter parts discuss the influence of historical memory on creating the collective discourses of KDMS and its civic engagements, ambitions and activities. The purpose of the paper is also to evaluate the role of religion and secularisation in KDMS agenda and also to discuss the ways how the ´christian heritage´ becames the source for arguments in political debates and opossitely how the christianity could be interpreted in the light of conservative and right oriented socio-economic and political worldview.
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Lee, Jina, Ji-Soo Kim, Hye-In Cho, So-Ra Jo, and Yeun-Kyu Jang. "JIB-04, a Pan-Inhibitor of Histone Demethylases, Targets Histone-Lysine-Demethylase-Dependent AKT Pathway, Leading to Cell Cycle Arrest and Inhibition of Cancer Stem-Like Cell Properties in Hepatocellular Carcinoma Cells." International Journal of Molecular Sciences 23, no. 14 (July 11, 2022): 7657. http://dx.doi.org/10.3390/ijms23147657.
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JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04.
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Liu, Oscar Hsin-Fu, Miika Kiema, Mustafa Beter, Seppo Ylä-Herttuala, Johanna P. Laakkonen, and Minna U. Kaikkonen. "Hypoxia-Mediated Regulation of Histone Demethylases Affects Angiogenesis-Associated Functions in Endothelial Cells." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 11 (November 2020): 2665–77. http://dx.doi.org/10.1161/atvbaha.120.315214.
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Objective: Previous studies have demonstrated that the expression of several lysine (K)-specific demethylases (KDMs) is induced by hypoxia. Here, we sought to investigate the exact mechanisms underlying this regulation and its functional implications for endothelial cell function, such as angiogenesis. Approach and Results: We analyzed the expression changes of KDMs under hypoxia and modulation of HIF (hypoxia-inducible factor) expression using GRO-Seq and RNA-Seq in endothelial cells. We provide evidence that the majority of the KDMs are induced at the level of nascent transcription mediated by the action of HIF-1α and HIF-2α. Importantly, we show that transcriptional changes at the level of initiation represent the major mechanism of gene activation. To delineate the epigenetic effects of hypoxia and HIF activation in normoxia, we analyzed the genome-wide changes of H3K27me3 using chromosome immunoprecipitation-Seq. We discovered a redistribution of H3K27me3 at ≈2000 to 3000 transcriptionally active loci nearby genes implicated in angiogenesis. Among these, we demonstrate that vascular endothelial growth factor A ( VEGFA ) expression is partly induced by KDM4B- and KDM6B-mediated demethylation of nearby regions. Knockdown of KDM4B and KDM6B decreased cell proliferation, tube formation, and endothelial sprouting while affecting hundreds of genes associated with angiogenesis. These findings provide novel insights into the regulation of KDMs by hypoxia and the epigenetic regulation of VEGFA-mediated angiogenesis. Conclusions: Our study describes an additional level of epigenetic regulation where hypoxia induces redistribution of H3K27me3 around genes implicated in proliferation and angiogenesis. More specifically, we demonstrate that KDM4B and KDM6B play a key role in modulating the expression of the major angiogenic driver VEGFA.
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Lee, Song Hee, Emily R. Albright, Jeong-Hee Lee, Derek Jacobs, and Robert F. Kalejta. "Cellular defense against latent colonization foiled by human cytomegalovirus UL138 protein." Science Advances 1, no. 10 (November 2015): e1501164. http://dx.doi.org/10.1126/sciadv.1501164.
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Intrinsic immune defenses mediated by restriction factors inhibit productive viral infections. Select viruses rapidly establish latent infections and, with gene expression profiles that imply cell-autonomous intrinsic defenses, may be the most effective immune control measure against latent reservoirs. We illustrate that lysine-specific demethylases (KDMs) are restriction factors that prevent human cytomegalovirus from establishing latency by removing repressive epigenetic modifications from histones associated with the viral major immediate early promoter (MIEP), stimulating the expression of a viral lytic phase target of cell-mediated adaptive immunity. The viral UL138 protein negates this defense by preventing KDM association with the MIEP. The presence of an intrinsic defense against latency and the emergence of a cognate neutralizing viral factor indicate that “arms races” between hosts and viruses over lifelong colonization exist at the cellular level.
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Xu, Ling, Yuhong Lu, Jing Lai, Wei Yu, Zhenyi Jin, Yan Xu, Jie Chen, et al. "Characteristics of the TCR Vbeta Repertoire and Identical Clonally Expanded T Cells in Chronic Myeloid Leukemia Patients in Advanced Phase with ABL Mutations." Blood 126, no. 23 (December 3, 2015): 5136. http://dx.doi.org/10.1182/blood.v126.23.5136.5136.
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Abstract Abstract Tumor specific or related antigen cytotoxic lymphocyte (CTL) have been identified in chronic myeloid leukemia patients, however, whether they are constituted by specific type of T cell receptor chains has not been illustrated so far. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vβ T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vβ repertoire in 5 CML patients in blast crisis (BC-CML) and one in acceleration phase (AP-CML) with ABL kinase domain mutations (KDMs) including T315I, E255K, F317L+S417Y, Y-253F and L387M+T-315A. Examination of TCR Vβ expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) combined with GeneScan analysis. Significantly skewed TCR Vβ repertoires were observed in those patients, and 4 to 8 oligoclonally expanded TCR Vβ subfamilies could be identified in each sample, which distributed in 15/24 different subfamilies (TCR Vβ4, Vβ5, Vβ6, β8, Vβ9, Vβ10, Vβ15, Vβ16, Vβ17, Vβ18, Vβ19, Vβ21, Vβ22, Vβ23, Vβ24). Intriguingly, a relatively highly expanded Vβ9 clone with the same length as CDR3 (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the other two CML patient in myeloid blast crisis (MBC-CML) or the one CML patients in accelerated phase. In conclusion, restricted TCR Vβ repertoire expression and decreased clone complexity was a general phenomenon in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency status of these patients, and clonally expanded Vβ9 T cell clones may represent a specific immune response to leukemia-associated antigens in LBC-CML patients. Disclosures Li: The Foundation for High-level Talents in Higher Education of Guangdong, China ([2013]246-54),and the Guangzhou Science and Technology Project Foundation (201510010211): Research Funding; National Natural Science Foundation of China (81270604, U1301226, and 81400109), the Guangdong Natural Science Foundation (S2013040016151 and S2013020012863): Research Funding.
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Arifuzzaman, Sarder, Mst Reshma Khatun, and Rabeya Khatun. "Emerging of lysine demethylases (KDMs): From pathophysiological insights to novel therapeutic opportunities." Biomedicine & Pharmacotherapy 129 (September 2020): 110392. http://dx.doi.org/10.1016/j.biopha.2020.110392.
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He, Xingrui, Hang Zhang, Yingqian Zhang, Yang Ye, Shuo Wang, Renren Bai, Tian Xie, and Xiang-Yang Ye. "Drug discovery of histone lysine demethylases (KDMs) inhibitors (progress from 2018 to present)." European Journal of Medicinal Chemistry 231 (March 2022): 114143. http://dx.doi.org/10.1016/j.ejmech.2022.114143.
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Tarhonskaya, Hanna, Anthony Tumber, Akane Kawamura, and Christopher J. Schofield. "In Vitro Enzyme Assays for JmjC-Domain-Containing Lysine Histone Demethylases (JmjC-KDMs)." Current Protocols in Pharmacology 80, no. 1 (March 2018): 3.15.1–3.15.12. http://dx.doi.org/10.1002/cpph.34.
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Carmichael, James, Laure Escoubet, Kate Lines, Konstantinos Mavrommatis, Deborah Mortensen, Rajesh V. Thakker, and Anjan Thakurta. "RF19 | PSUN349 Histone Eraser and Reader Targeting Epigenetic Inhibitors Are Effective in Pancreatic Neuroendocrine Tumours." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A897—A898. http://dx.doi.org/10.1210/jendso/bvac150.1859.
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Abstract Background The 5-year survival for metastatic pancreatic neuroendocrine tumours (PNETs) is <50%, and current therapies are not effective. Thus, there is an unmet clinical need for new therapies for patients with PNETs. PNETs frequently have mutations in chromatin remodelling genes, including in Multiple Endocrine Neoplasia type 1 (MEN1), encoding menin, which is mutated in up to 40% of sporadic PNETs, and is part of multiple histone modifying complexes including the SET1/MLL methyltransferases. Aim To examine multiple classes of epigenetic inhibitors and determine which may be effective in treating PNETs. Methods BON1 and QGP1 PNET cell lines, the bronchial NET cell line H727, and the non-NET cell line HEK293T were utilised to assess >150 small molecule inhibitors targeting: histone deacetylases (HDACs); histone acetyltransferases; histone demethylases (KDMs); histone methyltransferases; bromodomain-containing proteins; menin; and DNA methyltransferases (DNMTs). MTOR inhibitors, already used clinically for PNET patients, as well as drugs targeting other tumorigenic pathways e.g. the proto-oncogene SRC, were used as comparators. Efficacy of compounds was evaluated using the Cell Titer Blue cell viability assay, and the Caspase Glo 3/7 apoptosis assay. Results At a dose of 1mM for 7 days, 26 compounds (including HDAC, KDM, bromodomain and mTOR inhibitors) significantly decreased the viability of both the BON1 and QGP1 cell lines by >50%, compared to DMSO control treated cells. Upon increasing the dose to 10mM for 7 days, 34 additional compounds, making a total of 60 compounds (including inhibitors of menin and DNMTs), decreased viability of both BON1 and QGP1 cells by >50%; and 56 and 46 compounds also reduced viability of H727 and HEK293 cells by >50%, respectively. Apoptosis assays utilising the 60 above compounds, at 10mM for 7 days, revealed that 25, 18, 14, and 9 of them could increase apoptosis by >4-fold of BON1, QGP1, H727 and HEK293 cells, respectively. Ten compounds (2 KDM, 5 HDAC and 3 bromodomain inhibitors) that were effective in reducing viability by >50% as well as increasing apoptosis by >4-fold of NET cells, were selected for further dosing (0.1-10mM) and time course investigations (3-7 days). All 10 compounds significantly reduced viability of BON1 and QGP1 cells (p<0.01) after 3 days of treatment. The KDM and HDAC inhibitors showed the greatest efficacy, by significantly (p<0.05) reducing BON1 and QGP1 cell viability at as low as 25nM treatment for 3 days. The efficacy of bromodomain inhibitors was not attained until 1000nM treatment, however these inhibitors had very little effect on the non-NET HEK293 cells. Conclusions Compounds targeting HDACs, KDMs or bromodomain-containing proteins are effective in reducing viability by >50% and increasing apoptosis by >4-fold of NET cells, and thus provide novel agents for studying anti-cancer mechanisms and potential therapeutic options for PNETs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.
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Banelli, Barbara, Antonio Daga, Alessandra Forlani, Giorgio Allemanni, Daniela Marubbi, Maria Pia Pistillo, Aldo Profumo, and Massimo Romani. "Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells." Oncotarget 8, no. 21 (April 4, 2017): 34896–910. http://dx.doi.org/10.18632/oncotarget.16820.
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Koutsioumpa, Marina, Maria Hatziapostolou, Christos Polytarchou, Ezequiel J. Tolosa, Luciana L. Almada, Swapna Mahurkar-Joshi, Jennifer Williams, et al. "Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming." Gut 68, no. 7 (October 18, 2018): 1271–86. http://dx.doi.org/10.1136/gutjnl-2017-315690.
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ObjectiveDespite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis.DesignDNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo.ResultsWe define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates.ConclusionTogether our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.
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Kindrick, Jessica D., Peter J. Ratcliffe, WIlliam Doug Figg, and David R. Mole. "Abstract 3766: Correlating locus-specific changes in histone trimethylation and gene expression in hypoxia." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3766. http://dx.doi.org/10.1158/1538-7445.am2022-3766.
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Abstract Low oxygen availability (hypoxia) is a common feature of many solid tumors and is associated with poor prognosis and resistance to therapy. The main regulator of cellular responses to hypoxia is the transcription factor HIF (hypoxia-inducible factor). In addition, several histone lysine demethylases (KDMs) are 2-OG dependent dioxygenases and require oxygen for their activity. When oxygen availability is limited, the activity of these KDMs is inhibited leading to global histone hypermethylation, potentially altering gene expression. However, some KDMs are also known to be direct transcriptional targets of HIF, increasing their expression in hypoxia and counteracting this histone hypermethylation. Furthermore, HIF can facilitate recruitment of histone methyltransferase activity to chromatin in cis, leading to local increases in methylation status. Histone methylation can be associated with both gene activation and gene repression, and it remains unclear how the balance of these widespread changes relates to locus-specific regulation of gene expression. Furthermore, previous attempts to analyze regulation of histone methylation by ChIP-seq in hypoxia have not employed normalization methods that take into account global changes in histone modification. We have performed ChIP-seq analysis of histone trimethylation (H3K4me3, H3K9me3, H3K27me3 and H3K36me3) in PC3 prostate cancer cells incubated in normoxia or (16hrs, 1%) hypoxia. We have then examined the effects of the HIF-transcriptional pathway on these marks using the same cell line following deletion of HIF-1b to block the HIF response. We employ an integrated spike-in with drosophila chromatin to provide a normalization control. We then relate our findings to changes in gene expression using RNA-seq analysis, again normalized to a spike-in control. We observe global increases in all 4 histone trimethylations across the genome in hypoxia. In particular, we observe hypoxic increases in histone trimethylation at all gene loci. However, while basal levels of histone trimethylation correlated with basal transcript levels as previously reported, hypoxic increases in promoter-associated histone H3K4me3 trimethylation bore no relation to either the direction or magnitude of gene regulation in hypoxia. Although, more subtle increases were observed across the gene body at gene loci induced by hypoxia. These findings question the currently accepted model that changes in H3K4me3 instruct changes in transcription in hypoxia and suggest that the overall effect of histone trimethylation is a more subtle balance of competing effects. Citation Format: Jessica D. Kindrick, Peter J. Ratcliffe, WIlliam Doug Figg, David R. Mole. Correlating locus-specific changes in histone trimethylation and gene expression in hypoxia [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 3766.
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Carter, David M., Edgar Specker, Jessica Przygodda, Martin Neuenschwander, Jens Peter von Kries, Udo Heinemann, Marc Nazaré, and Ulrich Gohlke. "Identification of a Novel Benzimidazole Pyrazolone Scaffold That Inhibits KDM4 Lysine Demethylases and Reduces Proliferation of Prostate Cancer Cells." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 7 (March 27, 2017): 801–12. http://dx.doi.org/10.1177/2472555217699157.
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Human lysine demethylase (KDM) enzymes (KDM1–7) constitute an emerging class of therapeutic targets, with activities that support growth and development of metastatic disease. By interacting with and co-activating the androgen receptor, the KDM4 subfamily (KDM4A–E) promotes aggressive phenotypes of prostate cancer (PCa). Knockdown of KDM4 expression or inhibition of KDM4 enzyme activity reduces the proliferation of PCa cell lines and highlights inhibition of lysine demethylation as a possible therapeutic method for PCa treatment. To address this possibility, we screened the ChemBioNet small molecule library for inhibitors of the human KDM4E isoform and identified several compounds with IC50 values in the low micromolar range. Two hits, validated as active by an orthogonal enzyme-linked immunosorbent assay, displayed moderate selectivity toward the KDM4 subfamily and exhibited antiproliferative effects in cellular models of PCa. These compounds were further characterized by their ability to maintain the transcriptionally silent histone H3 tri-methyl K9 epigenetic mark at subcytotoxic concentrations. Taken together, these efforts identify and validate a hydroxyquinoline scaffold and a novel benzimidazole pyrazolone scaffold as tractable for entry into hit-to-lead chemical optimization campaigns.
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Reis, Linda M., Huban Atilla, Peter Kannu, Adele Schneider, Samuel Thompson, Tanya Bardakjian, and Elena V. Semina. "Distinct Roles of Histone Lysine Demethylases and Methyltransferases in Developmental Eye Disease." Genes 14, no. 1 (January 14, 2023): 216. http://dx.doi.org/10.3390/genes14010216.
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Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, termed congenital regulopathies. In this report, we present several lines of evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that individuals with structural eye defects, especially when accompanied by craniofacial, neurodevelopmental and growth abnormalities, should be examined for possible variants in these genes. We identified nine heterozygous damaging genetic variants in KMT2D (5) and four other histone lysine methyltransferases/demethylases (KMT2C, SETD1A/KMT2F, KDM6A and KDM5C) in unrelated families affected with developmental eye disease, such as Peters anomaly, sclerocornea, Axenfeld-Rieger spectrum, microphthalmia and coloboma. Two families were clinically diagnosed with Axenfeld-Rieger syndrome and two were diagnosed with Peters plus-like syndrome; others received no specific diagnosis prior to genetic testing. All nine alleles were novel and five of them occurred de novo; five variants resulted in premature truncation, three were missense changes and one was an in-frame deletion/insertion; and seven variants were categorized as pathogenic or likely pathogenic and two were variants of uncertain significance. This study expands the phenotypic spectra associated with KMT and KDM factors and highlights the importance of genetic testing for correct clinical diagnosis.
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Choi, Yong-Ho, Min-Woo Lee, and Kwang-Soo Shin. "The Lysine Demethylases KdmA and KdmB Differently Regulate Asexual Development, Stress Response, and Virulence in Aspergillus fumigatus." Journal of Fungi 8, no. 6 (May 31, 2022): 590. http://dx.doi.org/10.3390/jof8060590.
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Histone demethylases govern diverse cellular processes, including growth, development, and secondary metabolism. In the present study, we investigated the functions of two lysine demethylases, KdmA and KdmB, in the opportunistic human pathogenic fungus Aspergillus fumigatus. Experiments with mutants harboring deletions of genes encoding KdmA (ΔkdmA) and KdmB (ΔkdmB) showed that KdmA is necessary for normal growth and proper conidiation, whereas KdmB negatively regulates vegetative growth and conidiation. In both mutant strains, tolerance to H2O2 was significantly decreased, and the activities of both conidia-specific catalase (CatA) and mycelia-specific catalase (Cat1) were decreased. Both mutants had significantly increased sensitivity to the guanine nucleotide synthesis inhibitor 6-azauracil (6AU). The ΔkdmA mutant produced more gliotoxin (GT), but the virulence was not changed significantly in immunocompromised mice. In contrast, the production of GT and virulence were markedly reduced by the loss of kdmB. Comparative transcriptomic analyses revealed that the expression levels of developmental process-related genes and antioxidant activity-related genes were downregulated in both mutants. Taken together, we concluded that KdmA and KdmB have opposite roles in vegetative growth, asexual sporulation, and GT production. However, the two proteins were equally important for the development of resistance to 6AU.
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Staehle, Hans Felix, Heike Luise Pahl, and Jonas Samuel Jutzi. "The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies." Biomolecules 11, no. 12 (December 20, 2021): 1911. http://dx.doi.org/10.3390/biom11121911.
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Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.
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Benedetti, Rosaria, Carmela Dell’Aversana, Tommaso De Marchi, Dante Rotili, Ning Qing Liu, Boris Novakovic, Serena Boccella, et al. "Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer." Cancers 11, no. 12 (December 16, 2019): 2027. http://dx.doi.org/10.3390/cancers11122027.
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In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer.
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Tian, Yuzhen, Ruiyi Fan, and Jiwu Zeng. "Comprehensive Analysis of Jumonji Domain C Family from Citrus grandis and Expression Profilings in the Exocarps of “Huajuhong” (Citrus grandis “Tomentosa”) during Various Development Stages." Horticulturae 7, no. 12 (December 20, 2021): 592. http://dx.doi.org/10.3390/horticulturae7120592.
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Citrus grandis “Tomentosa” (“Huajuhong”) is a famous Traditional Chinese Medicine. In this study, a total of 18 jumonji C (JMJC) domain-containing proteins were identified from C. grandis. The 18 CgJMJCs were unevenly located on six chromosomes of C. grandis. Phylogenetic analysis revealed that they could be classified into five groups, namely KDM3, KDM4, KDM5, JMJC, and JMJD6. The domain structures and motif architectures in the five groups were diversified. Cis-acting elements on the promoters of 18 CgJMJC genes were also investigated, and the abscisic acid-responsive element (ABRE) was distributed on 15 CgJMJC genes. Furthermore, the expression profiles of 18 CgJMJCs members in the exocarps of three varieties of “Huajuhong”, for different developmental stages, were examined. The results were validated by quantitative real-time PCR (qRT-PCR). The present study provides a comprehensive characterization of JMJC domain-containing proteins in C. grandis and their expression patterns in the exocarps of C. grandis “Tomentosa” for three varieties with various development stages.
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Porta, A. Vilarrubí, J. J. Alburquerque Béjar, D. Trastulli, P. Llabata, E. Pros, A. Villanueva, O. Romero, and M. Sanchez-Cespedes. "EP1.14-39 BRG1 Deficient Cells Are Sensitive to the Inhibition of Specific Lysine Demethylases (KDMs) in Lung Cancer." Journal of Thoracic Oncology 14, no. 10 (October 2019): S1047. http://dx.doi.org/10.1016/j.jtho.2019.08.2324.
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Lin, Zi-Han, Yen-Fan Chan, Min-Hsiung Pan, Yen-Chen Tung, and Zheng-Yuan Su. "Aged Citrus Peel (Chenpi) Prevents Acetaminophen-Induced Hepatotoxicity by Epigenetically Regulating Nrf2 Pathway." American Journal of Chinese Medicine 47, no. 08 (January 2019): 1833–51. http://dx.doi.org/10.1142/s0192415x19500939.
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Excessive consumption of analgesic drug acetaminophen (APAP) can cause severe oxidative stress-mediated liver injury. Here, we investigated the protective effect and mechanism of aged citrus peel (Chenpi, CP), a Chinese herb usually used in foods in Asia, against APAP-induced hepatotoxicity. CP water (CP-WE), ethanolic (CP-EE), and water extraction residue ethanolic (CP-WREE) extracts were prepared. We found that CP-WREE contained higher content of bioactive flavonoids, including narirutin, nobiletin, and tangeretin, and more effectively enhanced the Nrf2 pathway in ARE-luciferase reporter gene transfected human HepG2-C8 cells. In mouse AML-12 hepatocytes, CP-WREE minimized APAP-induced damage and lipid peroxidation and increased mRNA and protein expressions of Nrf2 and its downstream defense enzymes (HO-1, NQO1, and UGT1A). CP-WREE also downregulated HDACs and DNMTs, upregulated KDMs, and increased the unmethylated Nrf2 promoter level. Additionally, CP-WREE blocked in vitro DNA methyltransferase activity. Taken together, CP-WREE might attenuate oxidative stress-induced hepatotoxicity through epigenetically regulating Nrf2-mediated cellular defense system.
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Kim, Yong Yean, Girma Woldemichael, Berkley Gryder, Silvia Pomella, Ranuka Sinniah, Josh Kowalczyk, Young Song, et al. "Abstract 703: Novel histone lysine demethylase inhibitors disrupt PAX3-FOXO1-driven transcriptional output in fusion-positive rhabdomyosarcoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 703. http://dx.doi.org/10.1158/1538-7445.am2022-703.
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Abstract BACKGROUND: The PAX3/7-FOXO1 (P3F) fusion transcription factor is the oncogenic driver in fusion-positive rhabdomyosarcoma (FP-RMS). P3F drives oncogenesis in FP-RMS through transcriptional modulation of downstream target genes. Thus, P3F represents a unique vulnerability in FP-RMS. A screen for inhibitors of P3F action identified novel histone lysine demethylase (KDM) inhibitors characterized in this study. MATERIALS/METHODS: A specific luciferase assay which monitors P3F activity was utilized to screen 62,643 compounds. The top candidate with unknown mechanism of action, PFI-63, and its analog PFI-90, were characterized. Western blotting was used to detect MYOG, PARP, and PAX3-FOXO1. KDM enzyme inhibition assays were conducted. Ligand-observed NMR analysis was used to determine binding of PFI-90 to KDM3B. KDM knockdown using CRISPRi was carried out. ChIP-seq analysis on H3K4me3, H3K9me2, H3K27me3, H3K27ac, and PAX3-FOXO1 was performed. Mouse xenograft models of FP-RMS were used to determine in vivo efficacy. RESULTS: 64 compounds that inhibited P3F activity without general inhibition of transcription or induction of cell death were further characterized. PFI-63 and a more water-soluble analog, PFI-90, were identified. GSEA of RNA-seq showed activation of apoptosis and myogenesis while P3F targets were repressed. Activation of apoptosis and myogenesis were validated by Western blotting showing PARP cleavage and increased MYOG levels, respectively. RNA-seq suggested that PFI-63 and PFI-90 were KDM inhibitors. In vitro enzymatic inhibition assays confirmed activity against multiple KDMs with most potent inhibition of KDM3B. Western analysis for methylation at H3K4 and H3K9 showed increases after PFI-90 treatment. NMR techniques confirmed biophysical binding of PFI-90 to KDM3B. RNA-seq of KDM knockdowns demonstrated that KDM3B knockdown most closely recapitulated PFI-90’s downregulation of P3F targets. Knockdown of KDM1A recapitulated PFI-90’s upregulation of myogenesis and apoptosis. ChIP-seq analysis showed increased levels of H3K9me2 at P3F sites while H3K4me3 was increased in muscle differentiation and apoptosis. In two different in vivo xenograft models of FP-RMS, PFI-90 treatment delayed tumor progression vs DMSO control. CONCLUSION: We identified novel multi-KDM inhibitors with highest potency for KDM3B. Downregulation of P3F by KDM3B inhibition is associated with increased H3K9me2 at P3F sites. PFI-90 also inhibits KDM1A which increases H3K4me3 at myogenesis and apoptosis genes. Thus, PFI-90 is a novel multi-KDM inhibitor whose biological effect on FP-RMS is by inhibition of KDM3B and KDM1A. Pre-clinical validation via FP-RMS xenograft models showed that PFI-90 delayed tumor progression. PFI-90 thus represents a promising novel compound for the treatment of FP-RMS, and potentially, other transcriptionally driven cancers. Citation Format: Yong Yean Kim, Girma Woldemichael, Berkley Gryder, Silvia Pomella, Ranuka Sinniah, Josh Kowalczyk, Young Song, Mehal Churiwal, Joseph Barchi, John Schneekloth, Xinyu Wen, Hsein-Chao Chou, Barry Okeefe, John Shern, Robert Hawley, Javed Khan. Novel histone lysine demethylase inhibitors disrupt PAX3-FOXO1-driven transcriptional output in fusion-positive rhabdomyosarcoma [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 703.
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Xie, Jiang, Jiamin Sun, Jiatai Feng, Fuzhang Yang, Jiao Wang, Tieqiao Wen, and Qing Nie. "Kernel Differential Subgraph Analysis to Reveal the Key Period Affecting Glioblastoma." Biomolecules 10, no. 2 (February 17, 2020): 318. http://dx.doi.org/10.3390/biom10020318.
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Glioblastoma (GBM) is a fast-growing type of malignant primary brain tumor. To explore the mechanisms in GBM, complex biological networks are used to reveal crucial changes among different biological states, which reflect on the development of living organisms. It is critical to discover the kernel differential subgraph (KDS) that leads to drastic changes. However, identifying the KDS is similar to the Steiner Tree problem that is an NP-hard problem. In this paper, we developed a criterion to explore the KDS (CKDS), which considered the connectivity and scale of KDS, the topological difference of nodes and function relevance between genes in the KDS. The CKDS algorithm was applied to simulated datasets and three single-cell RNA sequencing (scRNA-seq) datasets including GBM, fetal human cortical neurons (FHCN) and neural differentiation. Then we performed the network topology and functional enrichment analyses on the extracted KDSs. Compared with the state-of-art methods, the CKDS algorithm outperformed on simulated datasets to discover the KDSs. In the GBM and FHCN, seventeen genes (one biomarker, nine regulatory genes, one driver genes, six therapeutic targets) and KEGG pathways in KDSs were strongly supported by literature mining that they were highly interrelated with GBM. Moreover, focused on GBM, there were fifteen genes (including ten regulatory genes, three driver genes, one biomarkers, one therapeutic target) and KEGG pathways found in the KDS of neural differentiation process from activated neural stem cells (aNSC) to neural progenitor cells (NPC), while few genes and no pathway were found in the period from NPC to astrocytes (Ast). These experiments indicated that the process from aNSC to NPC is a key differentiation period affecting the development of GBM. Therefore, the CKDS algorithm provides a unique perspective in identifying cell-type-specific genes and KDSs.
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Maitra, Swati, Nitin Khandelwal, Scherazad Kootar, Pooja Sant, Salil S. Pathak, Sujatha Reddy, Annapoorna P. K., Upadhyayula Suryanarayana Murty, Sumana Chakravarty, and Arvind Kumar. "Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders." Brain Sciences 10, no. 11 (November 9, 2020): 833. http://dx.doi.org/10.3390/brainsci10110833.
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Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.
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Schütt, Jacqueline, Theresa Nägler, Tino Schenk, and Annamaria Brioli. "Investigating the Interplay between Myeloma Cells and Bone Marrow Stromal Cells in the Development of Drug Resistance: Dissecting the Role of Epigenetic Modifications." Cancers 13, no. 16 (August 13, 2021): 4069. http://dx.doi.org/10.3390/cancers13164069.
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Multiple Myeloma (MM) is a malignancy of plasma cells infiltrating the bone marrow (BM). Many studies have demonstrated the crucial involvement of bone marrow stromal cells in MM progression and drug resistance. Together with the BM microenvironment (BMME), epigenetics also plays a crucial role in MM development. A variety of epigenetic regulators, including histone acetyltransferases (HATs), histone methyltransferases (HMTs) and lysine demethylases (KDMs), are altered in MM, contributing to the disease progression and prognosis. In addition to histone modifications, DNA methylation also plays a crucial role. Among others, aberrant epigenetics involves processes associated with the BMME, like bone homeostasis, ECM remodeling or the development of treatment resistance. In this review, we will highlight the importance of the interplay of MM cells with the BMME in the development of treatment resistance. Additionally, we will focus on the epigenetic aberrations in MM and their role in disease evolution, interaction with the BMME, disease progression and development of drug resistance. We will also briefly touch on the epigenetic treatments currently available or currently under investigation to overcome BMME-driven treatment resistance.
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Kuo, Mei-Tsan, Isabelle Weber, Christa Fittschen, Luc Vereecken, and Jim Jr-Min Lin. "Kinetics of dimethyl sulfide (DMS) reactions with isoprene-derived Criegee intermediates studied with direct UV absorption." Atmospheric Chemistry and Physics 20, no. 21 (November 6, 2020): 12983–93. http://dx.doi.org/10.5194/acp-20-12983-2020.
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Abstract. Criegee intermediates (CIs) are formed in the ozonolysis of unsaturated hydrocarbons and play a role in atmospheric chemistry as a non-photolytic OH source or a strong oxidant. Using a relative rate method in an ozonolysis experiment, Newland et al. (2015) reported high reactivity of isoprene-derived Criegee intermediates towards dimethyl sulfide (DMS) relative to that towards SO2 with the ratio of the rate coefficients kDMS+CI/kSO2+CI = 3.5 ± 1.8. Here we reinvestigated the kinetics of DMS reactions with two major Criegee intermediates formed in isoprene ozonolysis, CH2OO, and methyl vinyl ketone oxide (MVKO). The individual CI was prepared following the reported photolytic method with suitable (diiodo) precursors in the presence of O2. The concentration of CH2OO or MVKO was monitored directly in real time through their intense UV–visible absorption. Our results indicate the reactions of DMS with CH2OO and MVKO are both very slow; the upper limits of the rate coefficients are 4 orders of magnitude smaller than the rate coefficient reported by Newland et al. (2015) These results suggest that the ozonolysis experiment could be complicated such that interpretation should be careful and these CIs would not oxidize atmospheric DMS at any substantial level.
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Liu, Mengshi, Jiacan Jiang, Yapeng Han, Mengying Shi, Xianli Li, Yingxiang Wang, Zhicheng Dong, and Cunyi Yang. "Functional Characterization of the Lysine-Specific Histone Demethylases Family in Soybean." Plants 11, no. 11 (May 25, 2022): 1398. http://dx.doi.org/10.3390/plants11111398.
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Histone modifications, such as methylation and demethylation, have crucial roles in regulating chromatin structure and gene expression. Lysine-specific histone demethylases (LSDs) belong to the amine oxidase family, which is an important family of histone lysine demethylases (KDMs), and functions in maintaining homeostasis of histone methylation. Here, we identified six LSD-like (LDL) genes from the important leguminous soybean. Phylogenetic analyses divided the six GmLDLs into four clusters with two highly conserved SWRIM and amine oxidase domains. Indeed, demethylase activity assay using recombinant GmLDL proteins in vitro demonstrated that GmLDLs have demethylase activity toward mono- and dimethylated Lys4 but not trimethylated histone 3, similar to their orthologs previously reported in animals. Using real-time PCR experiments in combination with public transcriptome data, we found that these six GmLDL genes exhibit comparable expressions in multiple tissues or in response to different abiotic stresses. Moreover, our genetic variation investigation of GmLDL genes among 761 resequenced soybean accessions indicates that GmLDLs are well conserved during soybean domestication and improvement. Taken together, these findings demonstrate that GmFLD, GmLDL1a, and GmLDL1b are bona fide H3K4 demethylases towards H4K4me1/2 and GmLDLs exist in various members with likely conserved and divergent roles in soybeans.
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Xie, Jiang, Dongfang Lu, Jiaxin Li, Jiao Wang, Yong Zhang, Yanhui Li, and Qing Nie. "Kernel differential subgraph reveals dynamic changes in biomolecular networks." Journal of Bioinformatics and Computational Biology 16, no. 01 (February 2018): 1750027. http://dx.doi.org/10.1142/s0219720017500275.
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Many major diseases, including various types of cancer, are increasingly threatening human health. However, the mechanisms of the dynamic processes underlying these diseases remain ambiguous. From the holistic perspective of systems science, complex biological networks can reveal biological phenomena. Changes among networks in different states influence the direction of living organisms. The identification of the kernel differential subgraph (KDS) that leads to drastic changes is critical. The existing studies contribute to the identification of a KDS in networks with the same nodes; however, networks in different states involve the disappearance of some nodes or the appearance of some new nodes. In this paper, we propose a new topology-based KDS (TKDS) method to explore the core module from gene regulatory networks with different nodes in this process. For the common nodes, the TKDS method considers the differential value (D-value) of the topological change. For the different nodes, TKDS identifies the most similar gene pairs and computes the D-value. Hence, TKDS discovers the essential KDS, which considers the relationships between the same nodes as well as different nodes. After applying this method to non-small cell lung cancer (NSCLC), we identified 30 genes that are most likely related to NSCLC and extracted the KDSs in both the cancer and normal states. Two significance functional modules were revealed, and gene ontology (GO) analyses and literature mining indicated that the KDSs are essential to the processes in NSCLC. In addition, compared with existing methods, TKDS provides a unique perspective in identifying particular genes and KDSs related to NSCLC. Moreover, TKDS has the potential to predict other critical disease-related genes and modules.
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Marandino, C. A., W. J. De Bruyn, S. D. Miller, and E. S. Saltzman. "Open ocean DMS air/sea fluxes over the eastern South Pacific Ocean." Atmospheric Chemistry and Physics Discussions 8, no. 3 (June 18, 2008): 12081–114. http://dx.doi.org/10.5194/acpd-8-12081-2008.
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Abstract. Air/sea fluxes of dimethylsulfide (DMS) were measured by eddy correlation over the Eastern South Pacific Ocean during January 2006. The cruise track extended from Manzanillo, Mexico, along 110° W, to Punta Arenas, Chile. Bulk air and surface ocean DMS levels were also measured and gas transfer coefficients (kDMS) were computed. Air and seawater DMS measurements were made using chemical ionization mass spectrometry (API-CIMS) and a gas/liquid membrane equilibrator. Mean surface seawater DMS concentrations were 3.8±2.2 nM and atmospheric mixing ratios were 340±370 ppt. The air/sea flux of DMS was uniformly out of the ocean, with an average value of 12±15 μmol m−2 d−1. Sea surface concentration and flux were highest around 15° S, in a region influenced by shelf waters and lowest around 25° S, in low chlorophyll gyre waters. The DMS gas transfer coefficient exhibited a linear wind speed-dependence over the wind speed range of 1 to 9 ms−1. This relationship is compared with previously derived of k from DMS, CO2, and dual tracer data from the Atlantic and Pacific Ocean, and with the NOAA/COARE gas transfer model. The model generated slope of k vs. wind speed is at the low end of those observed in previous DMS field studies.
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Shen, Zhenhua, Lin Huang, Suyu Jin, and Yucai Zheng. "Cloning and Expression Analysis of Two Kdm Lysine Demethylases in the Testes of Mature Yaks and Their Sterile Hybrids." Animals 10, no. 3 (March 20, 2020): 521. http://dx.doi.org/10.3390/ani10030521.
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The objective of this study was to explore the molecular mechanism for male sterility of yak hybrids based on two demethylases. Total RNA was extracted from the testes of adult yaks (n = 10) and yak hybrids (cattle–yaks, n = 10). The coding sequences (CDS) of two lysine demethylases (KDMs), KDM1A and KDM4B, were cloned by RT-PCR. The levels of KDM1A and KDM4B in yaks and cattle–yaks testes were detected using Real-time PCR and Western blotting for mRNA and protein, respectively. In addition, the histone methylation modifications of H3K36me3 and H3K27me3 were compared between testes of yaks and cattle–yaks using ELISA. The CDS of KDM1A and KDM4B were obtained from yak testes. The results showed that the CDS of KDM1A exhibited two variants: variant 1 has a CDS of 2622 bp, encoding 873 amino acids, while variant 2 has a CDS of 2562 bp, encoding 853 amino acids. The CDS of the KDM4B gene was 3351 bp in length, encoding 1116 amino acids. The mRNA and protein expression of KDM1A and KDM4B, as well as the level of H3K36me3, were dramatically decreased in the testes of cattle–yaks compared with yaks. The present results suggest that the male sterility of cattle–yaks might be associated with reduced histone methylation modifications.
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Pullen, J. K., M. D. Tallquist, R. W. Melvold, and L. R. Pease. "Recognition of a single amino acid change on the surface of a major transplantation antigen is in the context of self peptide." Journal of Immunology 152, no. 7 (April 1, 1994): 3445–52. http://dx.doi.org/10.4049/jimmunol.152.7.3445.
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Abstract The transcripts encoding two strongly alloantigenic class I mutant molecules, Kdm4 and Kdm5, were characterized and found to encode products that differ from the parental Kd glycoprotein by single amino acid substitutions. The Kdm4 molecule has an amino acid change at position 114, an integral component of a beta-sheet associated with pockets D and E of the peptide binding site. The basis for strong alloantigenicity of the variant molecule can be attributed to differences in peptide binding that were visualized by HPLC analysis of eluted peptides. In contrast, the Kdm5 molecule differs from the parent at position 158, a component of the alpha-helix that is not associated with any of the pockets of the peptide binding site. No differences in peptide binding by Kdm5 in comparison with the parent Kd molecule were seen by HPLC, suggesting that the variant and parent molecules bind the same set of peptides. The ability of (dm4 x dm5) F1 hybrid mice to recognize and lyse BALB/c stimulator cells indicates that the alloantigenic properties determined by the 158 substitution result from the interactions of the alpha-helix regions (changed in dm5) with the pockets of the binding site (changed in dm4). We conclude that self peptides shared by the F1 hybrid and the BALB/c stimulator cells are recognized in the context of structural features of the helices of the Ag-presenting molecule as alloantigenic determinants.
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Roggero, Carlos M., Victoria Esser, Lingling Duan, Allyson M. Rice, Shihong Ma, Ganesh V. Raj, Michael K. Rosen, Zhi-Ping Liu, and Josep Rizo. "Poly-glutamine-dependent self-association as a potential mechanism for regulation of androgen receptor activity." PLOS ONE 17, no. 1 (January 5, 2022): e0258876. http://dx.doi.org/10.1371/journal.pone.0258876.
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The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails extensive epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer, although they can lead to muscular atrophy. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC and muscular atrophy.
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Marandino, C. A., W. J. De Bruyn, S. D. Miller, and E. S. Saltzman. "Open ocean DMS air/sea fluxes over the eastern South Pacific Ocean." Atmospheric Chemistry and Physics 9, no. 2 (January 16, 2009): 345–56. http://dx.doi.org/10.5194/acp-9-345-2009.
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Abstract. Air/sea fluxes of dimethylsulfide (DMS) were measured by eddy correlation over the Eastern South Pacific Ocean during January 2006. The cruise track extended from Manzanillo, Mexico, along 110° W, to Punta Arenas, Chile. Bulk air and surface ocean DMS levels were also measured and gas transfer coefficients (kDMS) were computed. Air and seawater DMS measurements were made using chemical ionization mass spectrometry (API-CIMS) and a gas/liquid membrane equilibrator. Mean surface seawater DMS concentrations were 3.8±2.2 nM and atmospheric mixing ratios were 340±370 ppt. The air/sea flux of DMS was uniformly out of the ocean, with an average value of 12±15 μmol m−2 d−1. Sea surface concentration and flux were highest around 15° S, in a region influenced by shelf waters and lowest around 25° S, in low chlorophyll gyre waters. The DMS gas transfer coefficient exhibited a linear wind speed-dependence over the wind speed range of 1 to 9 m s−1. This relationship is compared with previously measured estimates of k from DMS, CO2, and dual tracer data from the Atlantic and Pacific Ocean, and with the NOAA/COARE gas transfer model. The model generated slope of k vs. wind speed is at the low end of those observed in previous DMS field studies.
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Tseng, Lin-Lu, Hsin-Hung Cheng, Ta-Sen Yeh, Shih-Chiang Huang, Ya-Yun Syu, Chih-Pin Chuu, Chiou-Hwa Yuh, Hsing-Jien Kung, and Wen-Ching Wang. "Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer." Proceedings of the National Academy of Sciences 117, no. 40 (September 21, 2020): 24859–66. http://dx.doi.org/10.1073/pnas.1919766117.
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Targeted treatments for advanced gastric cancer (GC) are needed, particularly for HER2-negative GC, which represents the majority of cases (80 to 88%). In this study, in silico analyses of the lysine histone demethylases (KDMs) involved in diverse biological processes and diseases revealed that PHD finger protein 8 (PHF8, KDM7B) was significantly associated with poor clinical outcome in HER2-negative GC. The depletion of PHF8 significantly reduced cancer progression in GC cells and in mouse xenografts. PHF8 regulated genes involved in cell migration/motility based on a microarray analysis. Of note, PHF8 interacted with c-Jun on the promoter of PRKCA which encodes PKCα. The depletion of PHF8 or PKCα greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a PKCα expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the PKCα-Src axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, PKCα, and PTEN showed a positive correlation between PHF8 and PKCα but negative correlations between PHF8 and PTEN and between PKCα and PTEN. Moreover, high PHF8-PKCα expression was significantly correlated with worse prognosis. Together, our results suggest that the PKCα-Src-PTEN pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC.
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Konduri, Purna Chaitanya, Tianyuan Wang, Narges Salamat, and Li Zhang. "Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins." Cells 9, no. 3 (March 22, 2020): 773. http://dx.doi.org/10.3390/cells9030773.
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The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation.
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Romani, Massimo, Antonio Daga, Alessandra Forlani, Maria Pia Pistillo, and Barbara Banelli. "Targeting of Histone Demethylases KDM5A and KDM6B Inhibits the Proliferation of Temozolomide-Resistant Glioblastoma Cells." Cancers 11, no. 6 (June 24, 2019): 878. http://dx.doi.org/10.3390/cancers11060878.
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Lysine histone demethylases (KDMs) are considered potential therapeutic targets in several tumors, including glioblastoma (GB). In particular, KDM5A is involved in the acquisition of temozolomide (TMZ) resistance in adult GB cells and UDX/KDM6B regulates H3K27 methylation, which is involved in the pediatric diffuse intrinsic pontine glioma (DIPG). Synthetic inhibitors of KDM5A (JIB 04 and CPI-455) efficiently block the proliferation of native and TMZ-resistant cells and the KDM6B inhibitor GSK J4 improves survival in a model of DIPG. The aim of our work was to determine if GSK J4 could be effective against GB cells that have acquired TMZ resistance and if it could synergize with TMZ or JIB 04 to increase the clinical utility of these molecules. Standard functional and pharmacological analytical procedures were utilized to determine the efficacy of the molecules under study when used alone or in combination against native GB cells and in a model of drug resistance. The results of this study indicated that although GSK J4 is active against native and TMZ-resistant cells, it does so at a lower efficacy than JIB 04. Drug combination studies revealed that GSK J4, differently from JIB 04, does not synergize with TMZ. Interestingly, GSK J4 and JIB 04 strongly synergize and are a potent combination against TMZ-resistant cells. Further studies in animal models will be necessary to determine if this combination of molecules might foster the development of novel therapeutic approaches for glioblastoma.
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Jin, Fengyan, Shaji K. Kumar, and Yun Dai. "The Lysine-Specific Demethylase KDM4A/JMJD2A Acts As a Tumor Suppressor in Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 191. http://dx.doi.org/10.1182/blood-2018-191.
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Abstract Introduction: Histone lysine methylation, a reversible event dynamically and reciprocally regulated by lysine methyltransferases (KMTs) and demethylases (KDMs), represents one of the major epigenetic mechanisms for regulation of chromatin remodeling and gene expression re-programming. The KDM4 family, which belongs to the Jumonji C (JmjC)-domain-containing proteins (JMJDs), consists of five members, including KDM4A-E that demethylate H3K9me2/3 and/or H3K36me2/3 in a Fe2+- and α-ketoglutarate-dependent manner. KDM4 proteins are involved in various cellular processes such as gene transcription and translation, DNA replication, DNA repair, apoptosis, and stem cell renewal. Notably, increasing evidence implicates KDM4 dysregulation in promoting genomic instabilities and oncogenesis, thereby which is considered as a potential target for emerging cancer epigenetic therapy. Although KDM4A, a member of the KDM4 family, has been widely studied in many solid tumors including breast, prostate, bladder cancer, its role in hematopoietic malignancies, including multiple myeloma (MM), remains unknown. Materials and Methods: Human MM cell lines (U266, RPMI8226, H929, OPM-2) were employed. After exposed to hypoxia (or the chemical hypoxia mimetic lactic acid) and anti-MM agents (e.g., bortezomib/Btz), cells were analyzed by flow cytometry, qPCR, Western blot to monitor apoptosis, cell cycle, proliferation (Ki67), DNA double-strand break/DSB (γH2A.X), expression of 1q21 and anti-apoptotic genes, as well as activation of the NF-κB and HIF pathways. The shRNA approach was used to knock down KDM4A for functional evaluation. The findings from in vitro experiments involving cell lines were then validated in primary MM samples to link KDM4A expression to disease progression and therapeutic response. Results: Analysis of the MM genome-wide GEP databases revealed that KDM4A mRNA was significantly up-regulated in MGUS and MM, but not SMM, compared to normal control, as well as in relapsed MM, compared to newly-diagnosed MM. To our surprise, KDM4A expression rather favored overall survival of MM patients, including those carrying 1q21 gain in whom KDM4A expression was indeed lower than those who did not have this high risk cytogenetic abnormality. Moreover, KDM4A expression correlated adversely with expression of 1q21 genes (e.g., CKS1B, MCL1, PSMD4, ARNT). Whereas basal KDM4A protein level was moderately but clearly higher in MM cell lines carrying 1q21 gain or acquired drug resistance than their counterparts, exposure to hypoxia or lactic acid (but not cobalt chloride) resulted in marked KDM4A up-regulation, accompanied by NF-κB and HIF pathway activation. However, while NF-κB inhibition and to a lesser extent ARNT/HIF-1β knockdown led to a robust increase in hypoxia-induced KDM4A expression, shRNA knockdown or pharmacological inhibition of KDM4A triggered NF-κB activation and HIF expression, as well as up-regulated anti-apoptotic proteins (e.g., Mcl-1, TNFAIP3/A20, CKS1B), in association with increased H3K36me3 rather than H3K9me3. Furthermore, KDM4A knockdown or inhibition sharply diminished Btz lethality and overrode hypoxia-mediated cytoprotection. Interestingly, KDM4A knockdown also increased MM cell proliferation, promoted S phase entry, and attenuated Btz-induced DSB. Last, IHC of sequential bone marrow biopsies revealed that while KDM4A protein was relatively low at diagnosis, its level was markedly increased when patients achieved CR and then fell to the baseline low level at relapse. Conclusion: KDM4A/JMJD2A, a lysine demethylase that has been recognized as an pro-oncogenic protein via its epigenetic and/or non-epigenetic properties, is identified for the first time as a potential tumor suppressor in MM, particularly in a high risk subtype carrying 1q21 gain. Whereas KDM4A is expressed in MM and can be further induced by hypoxia that naturally exists in bone marrow niche, it seems to play multiple inhibitory roles in cell growth, cell cycle, DNA repair, and drug resistance by suppressing expression of oncogenic and anti-apoptotic genes (especially 1q21 genes), likely via H3K36me3 demethylation, and antagonizing NF-κB and HIF activation. These findings suggest that in contrast to its pro-oncogenic role in certain solid tumors, KDM4A might instead act as a tumor suppressor in MM. This work was supported by NNSFC (81471165, 81670189, and 81670190). Disclosures Kumar: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Boila, Liberalis Debraj, Shankha Subhra Chatterjee, Debasis Banerjee, and Amitava Sengupta. "KDM6 and KDM4 histone lysine demethylases emerge as molecular therapeutic targets in human acute myeloid leukemia." Experimental Hematology 58 (February 2018): 44–51. http://dx.doi.org/10.1016/j.exphem.2017.10.002.
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Taylor-Papadimitriou, Joyce, and Joy M. Burchell. "Histone Methylases and Demethylases Regulating Antagonistic Methyl Marks: Changes Occurring in Cancer." Cells 11, no. 7 (March 25, 2022): 1113. http://dx.doi.org/10.3390/cells11071113.
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Epigenetic regulation of gene expression is crucial to the determination of cell fate in development and differentiation, and the Polycomb (PcG) and Trithorax (TrxG) groups of proteins, acting antagonistically as complexes, play a major role in this regulation. Although originally identified in Drosophila, these complexes are conserved in evolution and the components are well defined in mammals. Each complex contains a protein with methylase activity (KMT), which can add methyl groups to a specific lysine in histone tails, histone 3 lysine 27 (H3K27), by PcG complexes, and H3K4 and H3K36 by TrxG complexes, creating transcriptionally repressive or active marks, respectively. Histone demethylases (KDMs), identified later, added a new dimension to histone methylation, and mutations or changes in levels of expression are seen in both methylases and demethylases and in components of the PcG and TrX complexes across a range of cancers. In this review, we focus on both methylases and demethylases governing the methylation state of the suppressive and active marks and consider their action and interaction in normal tissues and in cancer. A picture is emerging which indicates that the changes which occur in cancer during methylation of histone lysines can lead to repression of genes, including tumour suppressor genes, or to the activation of oncogenes. Methylases or demethylases, which are themselves tumour suppressors, are highly mutated. Novel targets for cancer therapy have been identified and a methylase (KMT6A/EZH2), which produces the repressive H3K27me3 mark, and a demethylase (KDM1A/LSD1), which demethylates the active H3K4me2 mark, are now under clinical evaluation.
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Boila, Liberalis Debraj, Liqing Jin, Alex Murison, Subham K. Bandyopadhyay, Subhadeep Ghosh, Siva Sai Naga Anurag Muddineni, Andy G. X. Zeng, et al. "KDM6 Demethylases Integrate DNA Repair Gene Regulation: Loss of KDM6A Sensitizes AML to PARP Inhibition and Potentiates with BCL2 Blockade." Blood 138, Supplement 1 (November 5, 2021): 25. http://dx.doi.org/10.1182/blood-2021-145491.
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Abstract Acute myeloid leukemia (AML) is a heterogeneous, aggressive hematological malignancy with dismal prognosis where limited targeted therapies are currently available. Poly-(ADP-ribose)-polymerase (PARP) inhibition has emerged as an important therapeutic arsenal to target homologous recombination-deficient tumors. However, molecular understanding of PARP blockade in the context of epigenetic derangements and transcriptional plasticity in human elderly AML pathogenesis remains unexplored. KDM6 proteins are H3K27 demethylases that critically regulate chromatin architecture in multi-cellularity and tumorigenesis (Tran, Mol Cell Biol 2020). KDM6A escapes X-chr inactivation, and Utx-/- female mice spontaneously develop aging associated myeloid leukemia (Gozdecka, Nat Genet 2018; Sera, Blood 2021). In addition, KDM6A loss of function mutation is implicated in AML relapse (Stief, Leukemia 2020). In contrast, KDM6B primarily exerts an oncogenic function in heme-malignancies. Together, KDM6A and KDM6B play cell type-specific function in leukemia, and KDM6 proteins and associated signaling emerge as important focal point for developing molecular targeted therapy. We identify that KDM6 demethylase activity critically regulates DNA damage repair (DDR) gene expression program in AML. Transcriptome analysis indicated a significant downregulation of expression of DDR genesets in both KDM6A deficient human AML and Utx -/- pre-leukemic cells. Lentiviral shRNA screening performed in response to low-dose γ-irradiation in AML stem cells, revealed a radioprotective function of KDM6A. Expression of KDM6s is regulated by genotoxic stress in a time-dependent manner, and deficiency of JmjC catalytic function impaired DDR transcriptional activation and compromised repair potential. Mechanistically, quantitative ChIP experiments also revealed co-operation between KDM6A and SWI/SNF facilitating dynamic chromatin remodeling at TSS/promoter to induce DDR gene expression. To interrogate changes in chromatin accessibility we performed ATAC-seq analysis in KDM6 deficient AML. Motif enrichment highlighted that while KDM6A depletion led to reduced chromatin access to 140 transcription factors (TFs), only 56 TF binding sites showed increased accessibility. Overall, changes in chromatin accessibility, associated with a reduced binding of DDR regulatory TFs in KDM6 deficient AML, account for a compromised DDR function. In agreement with these findings an array of KDM6 deficient AML cells were more sensitive to PARP inhibition, and pre-clinical mice models xenotransplanted with KDM6A loss of function AML line showed an increased susceptibility to PARP blockade in vivo. FLT3-ITD positive AML with a lower KDM6A expression was more sensitive to olaparib. In addition, olaparib administration significantly reduced bone marrow engraftment of patient-derived xenografts of KDM6A-mutant primary AML. Interestingly, KDM6A expression is upregulated in venetoclax-resistant monocytic-AML compared to venet-sensitive primitive-AML. Using venet responsive isogenic lines we demonstrated that attenuation of KDM6 function increased mitochondrial activity, intracellular ROS levels, de-repressed BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6 loss resulted in transcriptional repression of BCL2A1, commonly associated with venet resistance (Zhang, Nat Cancer 2020). Corroborating these results, dual targeting of PARP with BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing primary AML apoptosis, and KDM6A loss further enhanced this synergism. In sum, our study illustrates a molecular mechanistic rationale in support for a novel combination targeted therapy for AML, and posit KDM6A as a molecular determinant for therapeutic efficacy. Intriguingly, KDM6A functions as a gatekeeper of BCL2 and BCL2A1 expression. Similar to TET2 although bi-allelic Utx loss causes evolution to myeloid neoplasms, minimal KDM6 activity is important for survival of human AML cells. KDM6s have been implicated in solid tumors, and both PARP and BCL2 inhibitors are being tested in cancer patients, underscoring a wider scope of application. To conclude, KDM6A unfolds to be a central regulator for susceptibility of AML to both PARP and BCL2 inhibition, expanding the possibility to characterize effective combination targeted therapy for AML in clinical settings. Disclosures Minden: Astellas: Consultancy. Dick: Celgene, Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Hou, Xuyang, Qiuguo Li, Leping Yang, Zhulin Yang, Jun He, Qinglong Li, and Daming Li. "KDM1A and KDM3A promote tumor growth by upregulating cell cycle-associated genes in pancreatic cancer." Experimental Biology and Medicine 246, no. 17 (June 25, 2021): 1869–83. http://dx.doi.org/10.1177/15353702211023473.
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Pancreatic cancer is a highly malignant cancer of the pancreas with a very poor prognosis. Methylation of histone lysine residues is essential for regulating cancer physiology and pathophysiology, mediated by a set of methyltransferases (KMTs) and demethylases (KDMs). This study surveyed the expression of methylation regulators functioning at lysine 9 of histone 3 (H3K9) in pancreatic lesions and explored the underlying mechanisms. We analyzed KDM1A and KDM3A expression in clinical samples by immunohistochemical staining and searching the TCGA PAAD program and GEO datasets. Next, we identified the variation in tumor growth in vitro and in vivo after knockdown of KDM1A or KDM3A and explored the downstream regulators of KDM1A and KDM3A via RNA-seq, and gain- and loss-of-function assays. Eleven H3K9 methylation regulators were highly expressed in pancreatic cancer, and only KDM1A and KDM3A expression positively correlated with the clinicopathological characteristics in pancreatic cancer. High expression of KDM1A or KDM3A positively correlated with pathological grade, lymphatic metastasis, invasion, and clinical stage. Kaplan–Meier analysis indicated that a higher level of KDM1A or KDM3A led to a shorter survival period. Knockdown of KDM1A or KDM3A led to markedly impaired tumor growth in vitro and in vivo. Mechanistically, CCNA2, a cell cycle-associated gene was partially responsible for KDM1A knockdown-mediated effect and CDK6, also a cell cycle-associated gene was partially responsible for KDM3A knockdown-mediated effect on pancreatic cancer cells. Our study demonstrates that KDM1A and KDM3A are highly expressed in pancreatic cancer and are intimately correlated with clinicopathological factors and prognosis. The mechanism of action of KDM1A or KDM3A was both linked to the regulation of cell cycle-associated genes, such as CCNA2 or CDK6, respectively, by an H3K9-dependent pathway.
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Besschetnova, Anna, Wanting Han, Mingyu Liu, Yanfei Gao, Muqing Li, Zifeng Wang, Maryam Labaf, et al. "Abstract A021: Lysine methylation in EHMT1/GLP acts as a molecular switch to reprogram transcription networks to drive prostate cancer progression." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): A021. http://dx.doi.org/10.1158/1538-7445.cancepi22-a021.
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Abstract Background: Prostate Cancer (PCa) progresses to a metastatic form of cancer called Castration-Resistant Prostate Cancer (CRPC) after treatment with androgen deprivation therapies (ADTs). Epigenetic reprogramming through altered expression and activity of histone modifier proteins is one major mechanism of tumor resistance. In particular, histone lysine methyltransferases (KMTs) and demethylases (KDMs) are important epigenetic targets in CRPC. In this study, we have focused on studying the function and regulation of Euchromatic Histone Methyltransferase 1 protein (EHMT1/GLP), which is a well-known H3K9 methyltransferase and functions in repressing gene transcription. EHMT family genes are altered in ~2-3% of primary PCa and ~10% of CRPC (primarily gene amplification) and their expression levels are significantly increased in CRPC, suggesting these proteins may have oncogenic activities in driving CRPC progression. Methods: We conducted an integrated analysis of ChIP-seq and RNA-seq analysis in LNCaP PCa cells to characterize the transcription program of EHMT1. We then performed proteomics analyses in VCaP and LNCaP PCa cells to identify post-translational modifications of EHMT1 and functionally validated the findings by generating loss-of-function mutations. We performed a histone demethylase assay to discover if EHMT1 is a substrate of LSD1 (a member of the KDM family). Moreover, we also assessed the effects of EHMT1 silencing or inhibition (in multiple PCa cell lines) on cell proliferation and metastasis in vitro using cell cycle analysis and transwell migration assay, and tumor growth and metastasis in vivo using mouse subcutaneous injection and zebrafish embryo injection approaches. Results: Our data showed that EHMT1 can transcriptionally activate multiple oncogenic pathways, including E2F and MYC signaling. Proteomic analyses revealed that EHMT1 is methylated in PCa cell lines, with dual-lysine methylation occurring at the K450/K451 sites. The histone demethylase assay showed that methylated K450, but not K451 is a potential substrate of LSD1. By generating the K450R, K451R, and K450/451R mutants, we showed that the K450/451R mutant, but not any single lysine mutants, can greatly expand EHMT1 chromatin binding independent of its H3K9 methyltransferase activity. This mutant also significantly induced EHMT1 oncogenic activity by activating E2F and MYC pathways. Moreover, EHMT1 silencing, or inhibition can significantly suppress tumor growth and metastasis. Conclusion: We have demonstrated that EHMT1 can function to activate oncogenic transcriptional programs in PCa by an H3K9-independent mechanism, possibly mediated through dual-lysine demethylation at K450/451 sites. Our data also suggest that targeting EHMT1 in CRPC may be a potential therapeutic strategy to suppress tumor growth and metastasis. Citation Format: Anna Besschetnova, Wanting Han, Mingyu Liu, Yanfei Gao, Muqing Li, Zifeng Wang, Maryam Labaf, Susan Patalano, Kavita Venkataramani, Rachel Muriph, Jill Macoska, Kellee Siegfried-Harris, Jason Evans, Steven Balk, Shuai Gao, Dong Han, Changmeng Cai. Lysine methylation in EHMT1/GLP acts as a molecular switch to reprogram transcription networks to drive prostate cancer progression. [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 A021.