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https://www.readbyqxmd.com/read/28068325/trim28-interacts-with-ezh2-and-swi-snf-to-activate-genes-that-promote-mammosphere-formation
#1
J Li, Y Xi, W Li, R L McCarthy, S A Stratton, W Zou, W Li, S Y Dent, A K Jain, M C Barton
Histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2) is generally associated with H3K27 methylation and gene silencing, as a member of the polycomb repressor 2 (PRC2) complex. Immunoprecipitation and mass spectrometry of the EZH2-protein interactome in estrogen receptor positive, breast cancer-derived MCF7 cells revealed EZH2 interactions with subunits of chromatin remodeler SWI/SNF complex and TRIM28, which formed a complex with EZH2 distinct from PRC2. Unexpectedly, transcriptome profiling showed that EZH2 primarily activates, rather than represses, transcription in MCF7 cells and with TRIM28 co-regulates a set of genes associated with stem cell maintenance and poor survival of breast cancer patients...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28044469/epigenetic-silencing-and-activation-of-transcription-influence-on-the-radiation-sensitivity-of-glioma-cell-lines
#2
A Sak, D Kübler, K Bannik, M Groneberg, S Strunz, R Kriehuber, M Stuschke
PURPOSE: To uncover the role of EZH2 and its opponent ASHL2, a polycomb and trithorax group protein, respectively on the radioresponsiveness of glioma cell lines. MATERIAL AND METHODS: Expression of EZH2 and ASHL2 was inhibited by siRNA in glioma cell lines. The effect on histone methylation, gene expression, DNA damage repair signaling, cell cycle checkpoints, apoptosis and tumor control were evaluated. RESULTS: Inhibition of EZH2 (EZH2i) led to a transcriptional dysregulation with upregulation of 544 and downregulation of 445 genes...
January 3, 2017: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/27983539/lncrna-ancr-down-regulation-suppresses-invasion-and-migration-of-colorectal-cancer-cells-by-regulating-ezh2-expression
#3
Zhao-Yang Yang, Fang Yang, Ying-Li Zhang, Bao Liu, Meng Wang, Xuan Hong, Yan Yu, Yao-Hui Zhou, Hai Zeng
Our study aimed to explore the effects of long noncoding RNA (lncRNA)-ANCR on the invasion and migration of colorectal cancer (CRC) cells by regulating enhancer of zeste homolog 2 (EZH2) expression. CRC tissues and adjacent normal tissues were collected and CRC SW620 cells line and normal human intestinal epithelial cells (HIECs) were incubated. CRC SW620 cells line was transfected with ANCR-siRNA. The expressions of ANCR and EZH2 mRNA were measured by real-time quantitative polymerase chain reaction (RT-qPCR)...
December 9, 2016: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/27941792/loss-of-the-histone-methyltransferase-ezh2-induces-resistance-to-multiple-drugs-in-acute-myeloid-leukemia
#4
Stefanie Göllner, Thomas Oellerich, Shuchi Agrawal-Singh, Tino Schenk, Hans-Ulrich Klein, Christian Rohde, Caroline Pabst, Tim Sauer, Mads Lerdrup, Sigal Tavor, Friedrich Stölzel, Sylvia Herold, Gerhard Ehninger, Gabriele Köhler, Kuan-Ting Pan, Henning Urlaub, Hubert Serve, Martin Dugas, Karsten Spiekermann, Binje Vick, Irmela Jeremias, Wolfgang E Berdel, Klaus Hansen, Arthur Zelent, Claudia Wickenhauser, Lutz P Müller, Christian Thiede, Carsten Müller-Tidow
In acute myeloid leukemia (AML), therapy resistance frequently occurs, leading to high mortality among patients. However, the mechanisms that render leukemic cells drug resistant remain largely undefined. Here, we identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors (TKIs) and cytotoxic drugs in AML. Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo...
January 2017: Nature Medicine
https://www.readbyqxmd.com/read/27927750/mdm2-as-a-chromatin-modifier
#5
REVIEW
Magdalena Wienken, Ute M Moll, Matthias Dobbelstein
Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb group (PcG) family. PcG proteins form polycomb repressive complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27) trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119) monoubiquitination. Both PRCs mostly support a compact and transcriptionally silent chromatin structure...
November 9, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27926872/deletion-of-the-polycomb-group-protein-ezh2-leads-to-compromised-self-renewal-and-differentiation-defects-in-human-embryonic-stem-cells
#6
Adam Collinson, Amanda J Collier, Natasha P Morgan, Arnold R Sienerth, Tamir Chandra, Simon Andrews, Peter J Rugg-Gunn
Through the histone methyltransferase EZH2, the Polycomb complex PRC2 mediates H3K27me3 and is associated with transcriptional repression. PRC2 regulates cell-fate decisions in model organisms; however, its role in regulating cell differentiation during human embryogenesis is unknown. Here, we report the characterization of EZH2-deficient human embryonic stem cells (hESCs). H3K27me3 was lost upon EZH2 deletion, identifying an essential requirement for EZH2 in methylating H3K27 in hESCs, in contrast to its non-essential role in mouse ESCs...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27923618/novel-3-methylindoline-inhibitors-of-ezh2-design-synthesis-and-sar
#7
Amantullah Ansari, Sharad Satalkar, Varshavekumar Patil, Amit S Shete, Simranjeet Kaur, Ashu Gupta, Siddhartha Singh, Mohd Raja, Daniel L Severance, Sebastián Bernales, Sarvajit Chakravarty, David T Hung, Son M Pham, Francisco J Herrera, Roopa Rai
EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27897169/ezh1-and-ezh2-promote-skeletal-growth-by-repressing-inhibitors-of-chondrocyte-proliferation-and-hypertrophy
#8
Julian C Lui, Presley Garrison, Quang Nguyen, Michal Ad, Chithra Keembiyehetty, Weiping Chen, Youn Hee Jee, Ellie Landman, Ola Nilsson, Kevin M Barnes, Jeffrey Baron
Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised...
November 29, 2016: Nature Communications
https://www.readbyqxmd.com/read/27852821/meg3-long-noncoding-rna-contributes-to-the-epigenetic-regulation-of-epithelial-mesenchymal-transition-in-lung-cancer-cell-lines
#9
Minoru Terashima, Shoichiro Tange, Akihiko Ishimura, Takeshi Suzuki
Histone methylation is implicated in a number of biological and pathological processes, including cancer development. In this study, we investigated the molecular mechanism for the recruitment of Polycomb repressive complex-2 (PRC2) and its accessory component, JARID2, to chromatin, which regulates methylation of lysine 27 of histone H3 (H3K27), during epithelial-mesenchymal transition (EMT) of cancer cells. The expression of MEG3 long noncoding RNA (lncRNA), which could interact with JARID2, was clearly increased during transforming growth factor-β (TGF-β)-induced EMT of human lung cancer cell lines...
January 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27845897/the-jazf1-suz12-fusion-protein-disrupts-prc2-complexes-and-impairs-chromatin-repression-during-human-endometrial-stromal-tumorogenesis
#10
Xianyong Ma, Jinglan Wang, Jianhui Wang, Charles X Ma, Xiaobin Gao, Vytas Patriub, Jeffrey L Sklar
The Polycomb repressive complex 2 (PRC2), which contains three core proteins EZH2, EED and SUZ12, controls chromatin compaction and transcription repression through trimethylation of lysine 27 on histone 3. The (7;17)(p15;q21) chromosomal translocation present in most cases of endometrial stromal sarcomas (ESSs) results in the in-frame fusion of the JAZF1 and SUZ12 genes. We have investigated whether and how the fusion protein JAZF1-SUZ12 functionally alters PRC2. We found that the fusion protein exists at high levels in ESS containing the t(7;17)...
November 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27830540/multifaceted-role-of-the-polycomb-group-gene-ezh2-in-hematological-malignancies
#11
REVIEW
Goro Sashida, Atsushi Iwama
Polycomb repressive complex (PRC) is a critical regulator of normal tissue homeostasis as well as tumorigenesis. EZH2, an enzymatic subunit of PRC2, is a histone H3K27 methyltransferase that functions in the regulation of gene silencing. EZH2 overexpression was first identified in prostate and breast cancers and is associated with poor clinical outcome. Subsequently, gain- and loss-of-function mutations of EZH2 have been identified in various tumors, including hematological malignancies, implicating EZH2 as either an oncogene or a tumor suppressor gene, depending on the cancer type...
November 9, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27783950/roles-of-h3k27me2-and-h3k27me3-examined-during-fate-specification-of-embryonic-stem-cells
#12
Aster H Juan, Stan Wang, Kyung Dae Ko, Hossein Zare, Pei-Fang Tsai, Xuesong Feng, Karinna O Vivanco, Anthony M Ascoli, Gustavo Gutierrez-Cruz, Jordan Krebs, Simone Sidoli, Adam L Knight, Roger A Pedersen, Benjamin A Garcia, Rafael Casellas, Jizhong Zou, Vittorio Sartorelli
The polycomb repressive complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/H3K27me3) have been interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs...
October 25, 2016: Cell Reports
https://www.readbyqxmd.com/read/27758858/enhancer-of-zeste-homolog-2-inhibition-stimulates-bone-formation-and-mitigates-bone-loss-caused-by-ovariectomy-in-skeletally-mature-mice
#13
Amel Dudakovic, Emily T Camilleri, Scott M Riester, Christopher R Paradise, Martina Gluscevic, Thomas M O'Toole, Roman Thaler, Jared M Evans, Huihuang Yan, Malayannan Subramaniam, John R Hawse, Gary S Stein, Martin A Montecino, Meghan E McGee-Lawrence, Jennifer J Westendorf, Andre J van Wijnen
Perturbations in skeletal development and bone degeneration may result in reduced bone mass and quality, leading to greater fracture risk. Bone loss is mitigated by bone protective therapies, but there is a clinical need for new bone-anabolic agents. Previous work has demonstrated that Ezh2 (enhancer of zeste homolog 2), a histone 3 lysine 27 (H3K27) methyltransferase, suppressed differentiation of osteogenic progenitors. Here, we investigated whether inhibition of Ezh2 can be leveraged for bone stimulatory applications...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27617932/regional-glutamine-deficiency-in-tumours-promotes-dedifferentiation-through-inhibition-of-histone%C3%A2-demethylation
#14
Min Pan, Michael A Reid, Xazmin H Lowman, Rajan P Kulkarni, Thai Q Tran, Xiaojing Liu, Ying Yang, Jenny E Hernandez-Davies, Kimberly K Rosales, Haiqing Li, Willy Hugo, Chunying Song, Xiangdong Xu, Dustin E Schones, David K Ann, Viviana Gradinaru, Roger S Lo, Jason W Locasale, Mei Kong
Poorly organized tumour vasculature often results in areas of limited nutrient supply and hypoxia. Despite our understanding of solid tumour responses to hypoxia, how nutrient deprivation regionally affects tumour growth and therapeutic response is poorly understood. Here, we show that the core region of solid tumours displayed glutamine deficiency compared with other amino acids. Low glutamine in tumour core regions led to dramatic histone hypermethylation due to decreased α-ketoglutarate levels, a key cofactor for the Jumonji-domain-containing histone demethylases...
October 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27578004/histone-h3k27-trimethylation-modulates-5-fluorouracil-resistance-by-inhibiting-pu-1-binding-to-the-dpyd-promoter
#15
Rentian Wu, Qian Nie, Erin E Tapper, Calvin R Jerde, Garrett S Dunlap, Shikshya Shrestha, Tarig A Elraiyah, Steven M Offer, Robert B Diasio
The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU response and toxicity. Although DPYD variants may affect 5-FU metabolism, they do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that H3K27 trimethylation (H3K27me3) at the DPYD promoter regulated by Ezh2 and UTX suppresses DPYD expression by inhibiting transcription factor PU...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27550047/long-non-coding-rna-hotair-expression-in-diffuse-large-b-cell-lymphoma-in-relation-to-polycomb-repressive-complex-pathway-proteins-and-h3k27-trimethylation
#16
Eun Ji Oh, Soo Hee Kim, Woo Ick Yang, Young Hyeh Ko, Sun Och Yoon
BACKGROUND: A long non-coding RNA hox transcript antisense intergenic RNA (HOTAIR) is involved in epigenetic regulation through chromatin remodeling by recruiting polycomb repressive complex 2 (PRC2) proteins (EZH2, SUZ12, and EED) that induce histone H3 trimethylation at lysine 27 (H3K27me3). Deregulation of c-MYC and interaction between c-MYC and EZH2 are well known in lymphomagenesis; however, little is known about the expression status of HOTAIR in diffuse large B-cell lymphomas (DLBCLs)...
September 2016: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/27494834/gsk3%C3%AE-inactivation-promotes-the-oncogenic-functions-of-ezh2-and-enhances-methylation-of-h3k27-in-human-breast-cancers
#17
How-Wen Ko, Heng-Huan Lee, Longfei Huo, Weiya Xia, Cheng-Chieh Yang, Jennifer L Hsu, Long-Yuan Li, Chien-Chen Lai, Li-Chuan Chan, Chien-Chia Cheng, Adam M Labaff, Hsin-Wei Liao, Seung-Oe Lim, Chia-Wei Li, Yongkun Wei, Lei Nie, Hirohito Yamaguchi, Mien-Chie Hung
During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. EZH2, a histone methyltransferase, promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. In this study, we show that glycogen synthase kinase 3 beta (GSK3β) negatively regulates H3K27 trimethylation...
August 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27490482/myc-activation-and-bcl2l11-silencing-by-a-tumour-virus-through-the-large-scale-reconfiguration-of-enhancer-promoter-hubs
#18
C David Wood, Hildegonda Veenstra, Sarika Khasnis, Andrea Gunnell, Helen M Webb, Claire Shannon-Lowe, Simon Andrews, Cameron S Osborne, Michelle J West
Lymphomagenesis in the presence of deregulated MYC requires suppression of MYC-driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein-Barr virus (EBV) activate MYC and silence BCL2L11. We show that the EBNA2 transactivator activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers and BRG1 is required for enhancer-promoter interactions in EBV-infected cells...
August 4, 2016: ELife
https://www.readbyqxmd.com/read/27468126/structure-activity-relationship-studies-for-enhancer-of-zeste-homologue-2-ezh2-and-enhancer-of-zeste-homologue-1-ezh1-inhibitors
#19
Xiaobao Yang, Fengling Li, Kyle D Konze, Jamel Meslamani, Anqi Ma, Peter J Brown, Ming-Ming Zhou, Cheryl H Arrowsmith, H Ümit Kaniskan, Masoud Vedadi, Jian Jin
EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias...
August 25, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27439608/epigenetic-role-of-nuclear-s6k1-in-early-adipogenesis
#20
Sang Ah Yi, Jihoon Han, Jeung-Whan Han
S6K1 is a key regulator of cell growth, cell size, and metabolism. Although the role of cytosolic S6K1 in cellular processes is well established, the function of S6K1 in the nucleus remains poorly understood. Our recent study has revealed that S6K1 is translocated into the nucleus upon adipogenic stimulus where it directly binds to and phosphorylates H2B at serine 36. Such phosphorylation promotes EZH2 recruitment and subsequent histone H3K27 trimethylation on the promoter of its target genes including Wnt6, Wnt10a, and Wnt10b, leading to repression of their expression...
August 2016: BMB Reports
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