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https://www.readbyqxmd.com/read/28581456/epigenetic-silencing-of-irf1-dysregulates-type-iii-interferon-responses-to-respiratory-virus-infection-in-epithelial-to-mesenchymal-transition
#1
Jun Yang, Bing Tian, Hong Sun, Roberto P Garofalo, Allan R Brasier
Chronic oxidative injury produced by airway disease triggers a transforming growth factor-β (TGF-β)-mediated epigenetic reprogramming known as the epithelial-mesenchymal transition (EMT). We observe that EMT silences protective mucosal interferon (IFN)-I and III production associated with enhanced rhinovirus (RV) and respiratory syncytial virus (RSV) replication. Mesenchymal transitioned cells are defective in inducible interferon regulatory factor 1 (IRF1) expression by occluding RelA and IRF3 access to the promoter...
June 5, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28556566/select-human-cancer-mutants-of-nrmt1-alter-its-catalytic-activity-and-decrease-n-terminal-trimethylation
#2
Kaitlyn M Shields, John G Tooley, Janusz J Petkowski, Daniel W Wilkey, Nichola C Garbett, Michael L Merchant, Alan Cheng, Christine E Schaner Tooley
A subset of B-cell lymphoma patients have dominant mutations in the histone H3 lysine 27 (H3K27) methyltransferase EZH2, which change it from a monomethylase to a trimethylase. These mutations occur in aromatic resides surrounding the active site and increase growth and alter transcription. We study the N-terminal trimethylase NRMT1 and the N-terminal monomethylase NRMT2. They are 50% identical, but differ in key aromatic residues in their active site. Given how these residues affect EZH2 activity, we tested whether they are responsible for the distinct catalytic activities of NRMT1/2...
May 27, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28529687/histone-demethylases-utx-and-jmjd3-are-required-for-nkt-cell-development-in-mice
#3
Daniel Northrup, Ryoji Yagi, Kairong Cui, William R Proctor, Chaochen Wang, Katarzyna Placek, Lance R Pohl, Rongfu Wang, Kai Ge, Jinfang Zhu, Keji Zhao
BACKGROUND: Natural killer (NK)T cells and conventional T cells share phenotypic characteristic however they differ in transcription factor requirements and functional properties. The role of histone modifying enzymes in conventional T cell development has been extensively studied, little is known about the function of enzymes regulating histone methylation in NKT cells. RESULTS: We show that conditional deletion of histone demethylases UTX and JMJD3 by CD4-Cre leads to near complete loss of liver NKT cells, while conventional T cells are less affected...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28522693/histone-h3-3k27m-represses-p16-to-accelerate-gliomagenesis-in-a-murine-model-of-dipg
#4
Francisco J Cordero, Zhiqing Huang, Carole Grenier, Xingyao He, Guo Hu, Roger E McLendon, Susan K Murphy, Rintaro Hashizume, Oren J Becher
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor genetically distinguished from adult GBM by the high prevalence of the K27M mutation in the histone H3 variant H3.3 (H3F3A). This mutation reprograms the H3K27me3 epigenetic landscape of DIPG by inhibiting the H3K27-specific histone methyltransferase EZH2. This globally reduces H3K27me2/3, critical repressive marks responsible for cell fate decisions, and also causes focal gain of H3K27me3 throughout the epigenome. To date, the tumor-driving effects of H3...
May 18, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28513825/loss-of-tet1-facilitates-dld1-colon-cancer-cell-migration-via-h3k27me3-mediated-down-regulation-of-e-cadherin
#5
Zhen Zhou, Hong-Sheng Zhang, Yang Liu, Zhong-Guo Zhang, Guang-Yuan Du, Hu Li, Xiao-Ying Yu, Ying-Hui Huang
Epigenetic modifications such as histone modifications and cytosine hydroxymethylation are linked to tumorigenesis. Loss of 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation 1 (TET1) down-regulation facilitates tumor initiation and development. However, the mechanisms by which loss of TET1 knockdown promotes malignancy development remains unclear. Here, we report that TET1 knockdown induced epithelial-mesenchymal transition (EMT) and increased cancer cell growth, migration and invasion in DLD1 cells...
May 17, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28490465/dual-inhibition-of-ezh2-and-ezh1-sensitizes-prc2-dependent-tumors-to-proteasome-inhibition
#6
Ola Rizq, Naoya Mimura, Motohiko Oshima, Atsunori Saraya, Shuhei Koide, Yuko Kato, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Changshan Wang, Tetsuhiro Chiba, Anqi Ma, Jian Jin, Tohru Iseki, Chiaki Nakaseko, Atsushi Iwama
<br /> <p>EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma (MM) and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on MM and prostate cancer.</p> <br /><br />Experimental Design: <br /> <p>In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in MM cell lines, primary patient cells and in a xenograft model...
May 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28485572/citrullination-methylation-crosstalk-on-histone-h3-regulates-er-target-gene-transcription
#7
Kathleen W Clancy, Anna-Maria Russell, Venkataraman Subramanian, Hannah Nguyen, Yuewei Qian, Robert M Campbell, Paul R Thompson
Posttranslational modifications of histone tails are a key contributor to epigenetic regulation. Histone H3 Arg26 and Lys27 are both modified by multiple enzymes, and their modifications have profound effects on gene expression. Citrullination of H3R26 by PAD2 and methylation of H3K27 by PRC2 have opposing downstream impacts on gene regulation; H3R26 citrullination activates gene expression, and H3K27 methylation represses gene expression. Both of these modifications are drivers of a variety of cancers, and their writer enzymes, PAD2 and EZH2, are the targets of drug therapies...
May 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28469799/histone-h3k14-hypoacetylation-and-h3k27-hypermethylation-along-with-hdac1-up-regulation-and-kdm6b-down-regulation-are-associated-with-active-pulmonary-tuberculosis-disease
#8
Yung-Che Chen, Tung-Ying Chao, Sum-Yee Leung, Chung-Jen Chen, Chao-Chien Wu, Wen-Feng Fang, Yi-Hsi Wang, Huang-Chih Chang, Ting-Ya Wang, Yong-Yong Lin, Yi-Xin Zheng, Meng-Chih Lin, Chang-Chun Hsiao
The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in active pulmonary tuberculosis (TB) disease. Global histone H3K27me3, H3K27me2, H3K9me3, H3K9Ac, and H3K14Ac expressions, and their modifying enzyme expressions, including KDM1A, KDM6B, EZH2, HDAC1, and HDAC2, were assessed in blood leukocytes from 81 patients with active pulmonary TB disease and 44 matched healthy subjects (HS). TLR2, TNF-α, IFN-γ, and IL12B-specific histone enrichment of peripheral blood mononuclear cells was measured by chromatin immunoprecipitation method...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28461508/conditional-knockin-of-dnmt3a-r878h-initiates-acute-myeloid-leukemia-with-mtor-pathway-involvement
#9
Yu-Jun Dai, Yue-Ying Wang, Jin-Yan Huang, Li Xia, Xiao-Dong Shi, Jie Xu, Jing Lu, Xian-Bin Su, Ying Yang, Wei-Na Zhang, Pan-Pan Wang, Song-Fang Wu, Ting Huang, Jian-Qing Mi, Ze-Guang Han, Zhu Chen, Sai-Juan Chen
DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin(-)Sca1(+)cKit(+) cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28445937/methylation-mediated-silencing-of-microrna-211-promotes-cell-growth-and-epithelial-to-mesenchymal-transition-through-activation-of-the-akt-%C3%AE-catenin-pathway-in-gbm
#10
Weidong Li, Xiaobo Miao, Lingling Liu, Yue Zhang, Xuejun Jin, Xiaojun Luo, Hai Gao, Xubin Deng
Aberrant expression of miR-211 has frequently been reported in cancer studies; however, its role in glioblastoma multiforme (GBM) has not been examined in detail. We investigated the function and the underlying mechanism of miR-211 in GBM. We revealed that miR-211 was downregulated in GBM tissues and cell lines. Restoration of miR-211 inhibited GBM cell growth and invasion both in vitro and in vivo. The epithelial to mesenchymal transition (EMT) phenotype was reversed when miR-211 expression was restored. HMGA2 was identified as a down-stream target of miR-211...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28438623/ezh2-overexpression-in-primary-gastrointestinal-diffuse-large-b-cell-lymphoma-and-its-association-with-the-clinicopathological-features
#11
Yang Liu, Kangjie Yu, Mingyang Li, Kaixuan Zeng, Jie Wei, Xia Li, Yixiong Liu, Danhui Zhao, Linni Fan, Zhou Yu, Yingmei Wang, Zengshan Li, Wei Zhang, Qingxian Bai, Qingguo Yan, Ying Guo, Zhe Wang, Shuangping Guo
Gastrointestinal diffuse large B cell lymphoma (GI DLBCL) is the most common gastrointestinal lymphoma, Enhancer of zeste homolog 2 (EZH2) have been implicated in the pathogenesis of several cancers. However, EZH2 has not been studied in GI DLBCL. Thus, we investigated EZH2 expression and EZH2 Y641 mutation in 100 GI DLBCL specimens by immunohistochemistry and sequencing. In addition, trimethylated H3K27 (H3K27me3), BCL2, c-MYC, and Ki-67 expression and Helicobacter pylori infection were detected, and BCL2 and c-MYC gene translocation were assessed...
April 21, 2017: Human Pathology
https://www.readbyqxmd.com/read/28430172/ezh2-alterations-in-follicular-lymphoma-biological-and-clinical-correlations
#12
S Huet, L Xerri, B Tesson, S Mareschal, S Taix, L Mescam-Mancini, E Sohier, M Carrère, J Lazarovici, O Casasnovas, L Tonon, S Boyault, S Hayette, C Haioun, B Fabiani, A Viari, F Jardin, G Salles
The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated...
April 21, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28419207/ckii-sirt1-sm22%C3%AE-loop-evokes-a-self-limited-inflammatory-response-in-vascular-smooth-muscle-cells
#13
Ya-Nan Shu, Li-Hua Dong, Han Li, Qian-Qian Pei, Sui-Bing Miao, Fan Zhang, Dan-Dan Zhang, Rong Chen, Ya-Juan Yin, Yan-Ling Lin, Zhen-Ying Xue, Pin Lv, Xiao-Li Xie, Li-Li Zhao, Xi Nie, Peng Chen, Mei Han
Aims: Sirtuin 1 (SIRT1) inhibits nuclear factor kappa B (NF-κB) activity in response to the inflammatory cytokine tumour necrosis factor alpha (TNF-α). Smooth muscle (SM) 22α is a phosphorylation-regulated suppressor of IKK-IκBα-NF-κB signalling cascades in vascular smooth muscle cells (VSMCs). Sm22α knockout results in increased expression of pro-inflammatory genes in the aortas which are controlled by NF-κB. This study aimed to investigate the relationship between SM22α and SIRT1 in the control of vascular inflammation...
April 16, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28418882/oncogenic-histone-methyltransferase-ezh2-a-novel-prognostic-marker-with-therapeutic-potential-in-endometrial-cancer
#14
Shinya Oki, Kenbun Sone, Katsutoshi Oda, Ryuji Hamamoto, Masako Ikemura, Daichi Maeda, Makoto Takeuchi, Michihiro Tanikawa, Mayuyo Mori-Uchino, Kazunori Nagasaka, Aki Miyasaka, Tomoko Kashiyama, Yuji Ikeda, Takahide Arimoto, Hiroyuki Kuramoto, Osamu Wada-Hiraike, Kei Kawana, Masashi Fukayama, Yutaka Osuga, Tomoyuki Fujii
The histone methyltransferase EZH2, a key epigenetic modifier, is known to be associated with human tumorigenesis. However, the physiological importance of EZH2 and its clinical relevance in endometrial cancer remain unclear. Hence, in the present study, we investigated the expression and function of EZH2 in endometrial cancer. In a quantitative real-time PCR analysis of 11 endometrial cancer cell lines and 52 clinical endometrial cancer specimens, EZH2 was significantly overexpressed in cancer cells and tissues compared to that in corresponding normal control cells and tissues...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28394193/ezh2-inhibitors-a-patent-review-2014-2016
#15
REVIEW
Giulia Stazi, Clemens Zwergel, Antonello Mai, Sergio Valente
The histone methyltransferase EZH2 is the catalytic subunit of the PRC2 complex involved in H3K27 trimethylation. Aberrant PRC2 activity has been reported in several cancers and EZH2 overexpression has been associated with poor outcome in different tumors. EZH2 somatic mutations and deletions was found in lymphomas, myelodysplastic and myeloproliferative disorders and associated with higher H3K27me3 levels. Numerous chemical entities have been studied as EZH2 inhibitors in the recent years and some of them entered the cancer clinical arena...
July 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28387316/lkb1-inactivation-drives-lung-cancer-lineage-switching-governed-by-polycomb-repressive-complex-2
#16
Haikuo Zhang, Christine Fillmore Brainson, Shohei Koyama, Amanda J Redig, Ting Chen, Shuai Li, Manav Gupta, Carolina Garcia-de-Alba, Margherita Paschini, Grit S Herter-Sprie, Gang Lu, Xin Zhang, Bryan P Marsh, Stephanie J Tuminello, Chunxiao Xu, Zhao Chen, Xiaoen Wang, Esra A Akbay, Mei Zheng, Sangeetha Palakurthi, Lynette M Sholl, Anil K Rustgi, David J Kwiatkowski, J Alan Diehl, Adam J Bass, Norman E Sharpless, Glenn Dranoff, Peter S Hammerman, Hongbin Ji, Nabeel Bardeesy, Dieter Saur, Hideo Watanabe, Carla F Kim, Kwok-Kin Wong
Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions...
April 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28329683/inactivation-of-ezh2-upregulates-gfi1-and-drives-aggressive-myc-driven-group-3-medulloblastoma
#17
BaoHan T Vo, Chunliang Li, Marc A Morgan, Ilan Theurillat, David Finkelstein, Shaela Wright, Judith Hyle, Stephanie M C Smith, Yiping Fan, Yong-Dong Wang, Gang Wu, Brent A Orr, Paul A Northcott, Ali Shilatifard, Charles J Sherr, Martine F Roussel
The most aggressive of four medulloblastoma (MB) subgroups are cMyc-driven group 3 (G3) tumors, some of which overexpress EZH2, the histone H3K27 mono-, di-, and trimethylase of polycomb-repressive complex 2. Ezh2 has a context-dependent role in different cancers as an oncogene or tumor suppressor and retards tumor progression in a mouse model of G3 MB. Engineered deletions of Ezh2 in G3 MBs by gene editing nucleases accelerated tumorigenesis, whereas Ezh2 re-expression reversed attendant histone modifications and slowed tumor progression...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28328977/jmjd3-aids-in-reprogramming-of-bone-marrow-progenitor-cells-to-hepatic-phenotype-through-epigenetic-activation-of-hepatic-transcription-factors
#18
Veena Kochat, Zaffar Equbal, Prakash Baligar, Vikash Kumar, Madhulika Srivastava, Asok Mukhopadhyay
The strictly regulated unidirectional differentiation program in some somatic stem/progenitor cells has been found to be modified in the ectopic site (tissue) undergoing regeneration. In these cases, the lineage barrier is crossed by either heterotypic cell fusion or direct differentiation. Though studies have shown the role of coordinated genetic and epigenetic mechanisms in cellular development and differentiation, how the lineage fate of adult bone marrow progenitor cells (BMPCs) is reprogrammed during liver regeneration and whether this lineage switch is stably maintained are not clearly understood...
2017: PloS One
https://www.readbyqxmd.com/read/28327608/kdm4b-histone-demethylase-and-g9a-regulate-expression-of-vascular-adhesion-proteins-in-cerebral-microvessels
#19
Ji-Young Choi, Sang-Sun Yoon, Sang-Eun Kim, Sangmee Ahn Jo
Intercellular adhesion molecule 1 (ICAM1) mediates the adhesion and transmigration of leukocytes across the endothelium, promoting inflammation. We investigated the epigenetic mechanism regulating ICAM1 expression. The pro-inflammatory cytokine TNF-α dramatically increased ICAM1 mRNA and protein levels in human brain microvascular endothelial cells and mouse brain microvessels. Chromatin immunoprecipitation revealed that TNF-α reduced methylation of histone H3 at lysines 9 and 27 (H3K9 and H3K27), well-known residues involved in gene suppression...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28323035/naturally-occurring-anti-cancer-agents-targeting-ezh2
#20
Fahimeh Shahabipour, Michele Caraglia, Muhammed Majeed, Giuseppe Derosa, Pamela Maffioli, Amirhossein Sahebkar
Natural products are considered as promising tools for the prevention and treatment of cancer. The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase unit of polycomb repressor complexes such as PRC2 complex that has oncogenic roles through interference with growth and metastatic potential. Several agents targeting EZH2 has been discovered but they often induce side effects in clinical trials. Recently, EZH2 has emerged as a potential target of natural products with documented anti-cancer effects and this discloses a new scenario for the development of EZH2 inhibitory strategies with agents with low cytotoxic detrimental effects...
March 18, 2017: Cancer Letters
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