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https://www.readbyqxmd.com/read/28811345/inhibitors-of-the-histone-methyltransferases-ezh2-1-induce-a-potent-antiviral-state-and-suppress-infection-by-diverse-viral-pathogens
#1
Jesse H Arbuckle, Paul J Gardina, David N Gordon, Heather D Hickman, Jonathan W Yewdell, Theodore C Pierson, Timothy G Myers, Thomas M Kristie
Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets used to treat a range of diseases, including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach used to control infection, persistence, and the resulting recurrent disease...
August 15, 2017: MBio
https://www.readbyqxmd.com/read/28795320/ezh2-promotes-cell-proliferation-by-regulating-the-expression-of-runx3-in-laryngeal-carcinoma
#2
Rong Lian, Huimin Ma, Zhiyan Wu, Guozheng Zhang, Lei Jiao, Wenjie Miao, Qianqian Jin, Ruixue Li, Ping Chen, Haixu Shi, Wenfa Yu
Enhancer of zeste homolog 2 (EZH2) is a highly conserved histone methyltransferase, which is overexpressed in different types of cancers such as breast and prostate cancer. It is reported that EZH2 can directly down-regulate RUNX3 by increasing histone H3 methylation. However, the role of EZH2 in the development and progression of laryngeal carcinoma has not yet been investigated, and the relationship between EZH2 and RUNX3 in laryngeal carcinoma is rarely reported. The current study aims to determine the role of EZH2 in the progression of laryngeal carcinoma, and investigate the interaction between EZH2 and the tumor suppressor RUNX3...
August 9, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28754964/enhancer-of-zeste-homolog-2-ezh2-induces-epithelial-mesenchymal-transition-in-endometriosis
#3
Qi Zhang, Peixin Dong, Xishi Liu, Noriaki Sakuragi, Sun-Wei Guo
EZH2, a subunit of the polycomb repressive complex 2 (PRC2) catalyzing trimethylation of histone H3 lysine 27 (H3K27), induces epithelial-mesenchymal transition (EMT) in cancers. However, whether EZH2 regulates EMT in endometriosis is unclear. Here, we show that EZH2 expression, along with its associated PRC2 proteins, is significantly elevated in ectopic and eutopic endometrium from women with endometriosis as compared with control endometrium. EZH2 knockdown or inhibition restored the epithelial phenotypes of endometriotic epithelial cells, concomitant with the upregulation of E-cadherin and downregulation of vimentin and transcription factors (Snail and Slug) as well as reduced cellular migratory and invasive propensity...
July 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28748258/ezh2-is-involved-in-silencing-of-wnt5a-during-epithelial-mesenchymal-transition-of-colon-cancer-cell-line
#4
Jianxin Tao, Liping Shi, Longchang Huang, Haoze Shi, Hang Chen, Yixin Wang, Tong Wang
PURPOSE: Transforming growth factor-β (TGF-β) induction of epithelial-mesenchymal transition (EMT) in SW480 was established as a system for studies of colon cancer metastasis. However, the epigenetic mechanisms underlying this process remain unknown. In mammal, polycomb repressive complex-2 (PRC2) is a highly conserved histone methyltransferase involved in epigenetic regulations. Enhancer of zeste Homolog 2 (EZH2) is the catalytic subunit of PRC2, which catalyzes methylation of lysine 27 of histone H3 (H3K27)...
July 26, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28705714/aristeromycin-and-dznep-cause-growth-inhibition-of-prostate-cancer-via-induction-of-mir-26a
#5
Noriko Uchiyama, Yukiya Tanaka, Tomohiro Kawamoto
Most prostate cancers initially respond to androgen deprivation therapy, but then progress from androgen-dependent to androgen-independent prostate cancers. In the present study, a differential cytotoxicity screen of hormone-resistant prostate cancer LNCaP-hr cells and the parental LNCaP-FGC cells against normal MRC5 fibroblast cells, identified a small molecule compound, Aristeromycin (a derivative of 3-deazaneplanocin A (DZNeP)). The molecular target was shown to be S-adenosylhomocysteine hydrolase (AHCY), which catalyzes reversible hydrolysis of S-adenosylhomocysteine (SAH) to adenosine and L-homocysteine...
July 10, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28698146/epigenetic-regulation-of-epithelial-mesenchymal-transition-by-kdm6a-histone-demethylase-in-lung-cancer-cells
#6
Minoru Terashima, Akihiko Ishimura, Sasithorn Wanna-Udom, Takeshi Suzuki
Histone methylation is associated with various biological and pathological processes including cancer development. KDM6A is a candidate tumor suppressor gene that encodes a histone H3 lysine 27 (H3K27) demethylase. In this study, we discovered that ectopic expression of KDM6A antagonized TGF-β-induced epithelial-mesenchymal transition (EMT) and cell migration of lung cancer cell lines through its demethylase activity. KDM6A counteracted TGF-β-dependent changes in the expression of EMT-related genes such as CDH1/E-cadherin, FN1/Fibronectin, ZEB family and microRNA-200 family...
September 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28581456/epigenetic-silencing-of-irf1-dysregulates-type-iii-interferon-responses-to-respiratory-virus-infection-in-epithelial-to-mesenchymal-transition
#7
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
#8
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...
August 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
#9
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
#10
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
#11
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 (5 hmC) 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
#12
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
Purpose: 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 and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on multiple myeloma and prostate cancer.Experimental Design:In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in multiple myeloma cell lines, primary patient cells, and in a xenograft model...
August 15, 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
#13
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...
June 16, 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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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