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https://www.readbyqxmd.com/read/29789597/enhancer-of-zeste-homolog-2-catalysed-h3k27-trimethylation-plays-a-key-role-in-acute-on-chronic-liver-failure-via-tnf-mediated-pathway
#1
Tianhui Zhou, Ye Sun, Ming Li, Yongsen Ding, Rongkun Yin, Ziqiang Li, Qing Xie, Shisan Bao, Wei Cai
Acute-on-chronic liver failure is mainly due to host immunity self-destruction. The histone H3 lysine 27 (H3K27) trimethylating enzyme, enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and regulates immunity, also involves pathogenesis of several liver diseases. The current study was to determine the role of methyltransferase EZH2 and its catalysed H3K27 trimethylation (H3K27me3) in liver failure, and to further investigate the potential target for liver failure treatment...
May 22, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29774113/ezh2-inhibitors-sensitize-myeloma-cell-lines-to-panobinostat-resulting-in-unique-combinatorial-transcriptomic-changes
#2
Taylor Harding, Jessica Swanson, Brian Van Ness
Multiple myeloma (MM) remains a largely incurable hematologic cancer due to an inability to broadly target inevitable drug-resistant relapse. Epigenetic abnormalities are abundantly present in multiple myeloma and have increasingly demonstrated critical roles for tumor development and relapse to standard therapies. Accumulating evidence suggests that the histone methyltransferase EZH2 is aberrantly active in MM. We tested the efficacy of EZH2 specific inhibitors in a large panel of human MM cell lines (HMCLs) and found that only a subset of HMCLs demonstrate single agent sensitivity despite ubiquitous global H3K27 demethylation...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29745807/epigenetic-remodeling-and-modification-to-preserve-skeletogenesis-in-vivo
#3
Tanner C Godfrey, Benjamin J Wildman, Amjad Javed, Christopher J Lengner, Mohammad Quamarul Hassan
Current studies offer little insight on how epigenetic remodeling of bone-specific chromatin maintains bone mass in vivo. Understanding this gap and precise mechanism is pivotal for future therapeutic innovation to prevent bone loss. Recently, we found that low bone mass is associated with decreased H3K27 acetylation (activating histone modification) of bone specific gene promoters. Here, we aim to elucidate the epigenetic mechanisms by which a miRNA cluster controls bone synthesis and homeostasis by regulating chromatin accessibility and H3K27 acetylation...
December 2018: Connective Tissue Research
https://www.readbyqxmd.com/read/29743723/dysregulation-of-ezh2-mir-138-axis-contributes-to-drug-resistance-in-multiple-myeloma-by-downregulating-rbpms
#4
Nasrin Rastgoo, Maryam Pourabdollah, Jahangir Abdi, Donna Reece, Hong Chang
EZH2 is highly expressed in multiple myeloma (MM). However, the molecular mechanisms underlying EZH2 overexpression and its role in drug resistance of MM remain undefined. Here we show that EZH2 is upregulated in drug-resistant MM cells and its aberrant overexpression is associated with poor prognosis of MM patients. Overexpression of EZH2 in parental MM cells renders them resistant to anti-myeloma drugs and suppression of EZH2 displays the opposite effects. Using miRNA target scan algorithms, we identify miR-138 as a regulator of EZH2, which is conversely repressed by EZH2-induced H3K27 trimethylation in MM-resistant cell lines and primary tumor cells...
April 24, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29726819/histone-methyltransferase-ezh2-a-therapeutic-target-for-ovarian-cancer
#5
REVIEW
Bayley A Jones, Sooryanarayana Varambally, Rebecca C Arend
Ovarian cancer is the fifth leading cause of cancer-related deaths in females in the United States. There were an estimated 22,440 new cases and 14,080 deaths due to ovarian cancer in 2017. Most patients present with advanced-stage disease, revealing the urgent need for new therapeutic strategies targeting pathways of tumorigenesis and chemotherapy resistance. While multiple genomic changes contribute to the progression of this aggressive disease, it has become increasingly evident that epigenetic events play a pivotal role in ovarian cancer development...
March 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29681498/distinct-stimulatory-mechanisms-regulate-the-catalytic-activity-of-polycomb-repressive-complex-2
#6
Chul-Hwan Lee, Marlene Holder, Daniel Grau, Ricardo Saldaña-Meyer, Jia-Ray Yu, Rais Ahmad Ganai, Jenny Zhang, Miao Wang, Gary LeRoy, Marc-Werner Dobenecker, Danny Reinberg, Karim-Jean Armache
The maintenance of gene expression patterns during metazoan development is achieved, in part, by the actions of polycomb repressive complex 2 (PRC2). PRC2 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. Whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze mono- and dimethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze trimethylation of H3K27 in mouse embryonic stem cells (mESCs)...
April 13, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29643989/the-lncrna-h19-positively-affects-the-tumorigenic-properties-of-glioblastoma-cells-and-contributes-to-nkd1-repression-through-the-recruitment-of-ezh2-on-its-promoter
#7
Barbara Fazi, Sabrina Garbo, Nicola Toschi, Annunziato Mangiola, Malinska Lombari, Daria Sicari, Cecilia Battistelli, Silvia Galardi, Alessandro Michienzi, Gianluca Trevisi, Rona Harari-Steinfeld, Carla Cicchini, Silvia Anna Ciafrè
The still largely obscure molecular events in the glioblastoma oncogenesis, a primary brain tumor characterized by an inevitably dismal prognosis, impel for investigation. The importance of Long noncoding RNAs as regulators of gene expression has recently become evident. Among them, H19 has a recognized oncogenic role in several types of human tumors and was shown to correlate to some oncogenic aspects of glioblastoma cells. Here we, hypothesyze that in glioblastoma H19 exerts its function through the interaction with the catalytic subunit of the PRC2 complex, EZH2...
March 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29626115/macrophage-microglial-ezh2-facilitates-autoimmune-inflammation-through-inhibition-of-socs3
#8
Xingli Zhang, Yan Wang, Jia Yuan, Ni Li, Siyu Pei, Jing Xu, Xuan Luo, Chaoming Mao, Junli Liu, Tao Yu, Shucheng Gan, Qianqian Zheng, Yinming Liang, Weixiang Guo, Ju Qiu, Gabriela Constantin, Jin Jin, Jun Qin, Yichuan Xiao
Histone 3 Lys27 (H3K27) trimethyltransferase Ezh2 is implicated in the pathogenesis of autoimmune inflammation. Nevertheless, the role of Ezh2 in macrophage/microglial activation remains to be defined. In this study, we identified that macrophage/microglial H3K27me3 or Ezh2, rather than functioning as a repressor, mediates toll-like receptor (TLR)-induced proinflammatory gene expression, and therefore Ezh2 depletion diminishes macrophage/microglial activation and attenuates the autoimmune inflammation in dextran sulfate sodium-induced colitis and experimental autoimmune encephalomyelitis...
April 6, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29620187/metformin-inhibits-ovarian-cancer-via-decreasing-h3k27-trimethylation
#9
Guiju Tang, Jianfeng Guo, Yapei Zhu, Zaiju Huang, Ting Liu, Jing Cai, Lili Yu, Zehua Wang
Metformin has been used for the treatment of type II diabetes mellitus for decades. Recently, used of metformin in the therapy of diverse human cancer types has received widespread attention, while the underlying mechanisms have been not fully elucidated. In the current study, 5-ethynyl-20-deoxyuridine assay to detect cell proliferation, flow cytometry to detect apoptosis, scratch wound healing and Transwell migration assay to detect cell migration capacity. The current study reported that metformin inhibited cell proliferation and migration, and promoted apoptosis in ovarian cancer cells, particularly under normoglycemic conditions in vitro...
March 29, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29606589/the-h3k36me2-methyltransferase-nsd1-demarcates-prc2-mediated-h3k27me2-and-h3k27me3-domains-in-embryonic-stem-cells
#10
Gundula Streubel, Ariane Watson, Sri Ganesh Jammula, Andrea Scelfo, Darren J Fitzpatrick, Giorgio Oliviero, Rachel McCole, Eric Conway, Eleanor Glancy, Gian Luca Negri, Eugene Dillon, Kieran Wynne, Diego Pasini, Nevan J Krogan, Adrian P Bracken, Gerard Cagney
The Polycomb repressor complex 2 (PRC2) is composed of the core subunits Ezh1/2, Suz12, and Eed, and it mediates all di- and tri-methylation of histone H3 at lysine 27 in higher eukaryotes. However, little is known about how the catalytic activity of PRC2 is regulated to demarcate H3K27me2 and H3K27me3 domains across the genome. To address this, we mapped the endogenous interactomes of Ezh2 and Suz12 in embryonic stem cells (ESCs), and we combined this with a functional screen for H3K27 methylation marks. We found that Nsd1-mediated H3K36me2 co-locates with H3K27me2, and its loss leads to genome-wide expansion of H3K27me3...
April 19, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29542684/exosomes-from-suxiao-jiuxin-pill-treated-cardiac-mesenchymal-stem-cells-decrease-h3k27-demethylase-utx-expression-in-mouse-cardiomyocytes-in-vitro
#11
Xiao-Fen Ruan, Yong-Jun Li, Cheng-Wei Ju, Yan Shen, Wei Lei, Can Chen, Yang Li, Hong Yu, Yu-Tao Liu, Il-Man Kim, Xiao-Long Wang, Neal L Weintraub, Yaoliang Tang
Suxiao Jiuxin pill (SJP) is a traditional Chinese medicine for the treatment of acute coronary syndrome in China, which contains two principal components, tetramethylpyrazine (TMP) and borneol (BOR). Thus far, however, the molecular mechanisms underlying the beneficial effects of SJP on the cardiac microenvironment are unknown. Cardiac mesenchymal stem cells (C-MSCs) communicate with cardiomyocytes (CMs) through the release of microvesicles (exosomes) to restore cardiac homeostasis and elicit repair, in part through epigenetic regulatory mechanisms...
April 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29529600/long-noncoding-rna-meg3-regulates-mafa-expression-in-mouse-beta-cells-by-inactivating-rad21-smc3-or-sin3%C3%AE
#12
Ning Wang, Yanan Zhu, Min Xie, Lintao Wang, Feiyan Jin, Yihui Li, Qingxin Yuan, Wei De
BACKGROUND/AIMS: The main pathogenic mechanism of diabetes is a decrease in the number of islet beta cells or a decline in their function. Recent studies have shown that pancreatic long noncoding RNAs (lncRNAs) have a high degree of tissue specificity and may be involved in the maintenance of islet cells function and the development of diabetes. The aim of this study was to investigate the molecular regulatory mechanism of mouse maternal expressed gene 3 (Meg3) in insulin biosynthesis in pancreatic islets...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29465369/altered-gene-expression-profiles-of-histone-lysine-methyltransferases-and-demethylases-in-rheumatoid-arthritis-synovial-fibroblasts
#13
Yasuto Araki, Yoshimi Aizaki, Kojiro Sato, Hiromi Oda, Riki Kurokawa, Toshihide Mimura
OBJECTIVES: Aberrant histone lysine methylation (HKM) has been reported in rheumatoid arthritis (RA) synovial fibroblasts (SFs). As histone lysine methyltransferases (HKMTs) and demethylases (HKDMs) regulate HKM, these enzymes are believed to be dysregulated in RASFs. The aim of this study is to clarify whether gene expressions of HKMTs and HKDMs are altered in RASFs. METHODS: SFs were isolated from synovial tissues obtained from RA or osteoarthritis (OA) patients during total knee joint replacement...
March 2018: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/29432129/identification-of-two-distinct-classes-of-the-human-ino80-complex-genome-wide
#14
John S Runge, Jesse R Raab, Terry Magnuson
Chromatin remodeling and histone modifying enzymes play a critical role in shaping the regulatory output of a cell. Although much is known about these classes of proteins, identifying the mechanisms by which they coordinate gene expression programs remains an exciting topic of investigation. One factor that may contribute to the targeting and activity of chromatin regulators is local chromatin landscape. We leveraged genomic approaches and publically-available datasets to characterize the chromatin landscape at targets of the human INO80 chromatin remodeling complex (INO80-C)...
March 28, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29379165/muc1-c-activates-polycomb-repressive-complexes-and-downregulates-tumor-suppressor-genes-in-human-cancer-cells
#15
REVIEW
Hasan Rajabi, Masayuki Hiraki, Donald Kufe
The PRC2 and PRC1 complexes are aberrantly expressed in human cancers and have been linked to decreases in patient survival. MUC1-C is an oncoprotein that is also overexpressed in diverse human cancers and is associated with a poor prognosis. Recent studies have supported a previously unreported function for MUC1-C in activating PRC2 and PRC1 in cancer cells. In the regulation of PRC2, MUC1-C (i) drives transcription of the EZH2 gene, (ii) binds directly to EZH2, and (iii) enhances occupancy of EZH2 on target gene promoters with an increase in H3K27 trimethylation...
April 2018: Oncogene
https://www.readbyqxmd.com/read/29378702/dnd1-mediated-epigenetic-control-of-teratoma-formation-in-mouse
#16
Wei Gu, Kentaro Mochizuki, Kei Otsuka, Ryohei Hamada, Asuka Takehara, Yasuhisa Matsui
Spontaneous testicular teratoma develops from primordial germ cells (PGCs) in embryos; however, the molecular mechanisms underlying teratoma formation are not fully understood. Mutation of the dead-end 1 ( Dnd1 ) gene, which encodes an RNA-binding protein, drastically enhances teratoma formation in the 129/Sv mouse strain. To elucidate the mechanism of Dnd1 mutation-induced teratoma formation, we focused on histone H3 lysine 27 (H3K27) trimethylation (me3), and found that the levels of H3K27me3 and its responsible methyltransferase, enhancer of zeste homolog 2 (Ezh2), were decreased in the teratoma-forming cells of Dnd1 mutant embryos...
January 29, 2018: Biology Open
https://www.readbyqxmd.com/read/29371630/necessity-of-p53-binding-to-the-cdh1-locus-for-its-expression-defines-two-epithelial-cell-types-differing-in-their-integrity
#17
Tsukasa Oikawa, Yutaro Otsuka, Yasuhito Onodera, Mei Horikawa, Haruka Handa, Shigeru Hashimoto, Yutaka Suzuki, Hisataka Sabe
TP53 mutation (i.e., loss of normal-p53) may evoke epithelial-mesenchymal transition (EMT), which was previously attributed to loss of certain miRNAs. However, not all epithelial cells undergo EMT upon TP53 mutation, and the p53-miRNA axis may not fully explain p53 function in epithelial integrity. We here show two modes of epithelial integrity: one involves p53-binding to a nucleotide region and the other does not. In the former, p53 binds to the CDH1 (encoding E-cadherin) locus to antagonize EZH2-mediated H3K27 trimethylation (H3K27me3) to maintain high levels of acetylation of H3K27 (H3K27ac)...
January 25, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29316949/ezh2-promotes-hepatocellular-carcinoma-progression-through-modulating-mir-22-galectin-9-axis
#18
Shaofei Chen, Jiarui Pu, Jie Bai, Yuping Yin, Ke Wu, Jiliang Wang, Xiaoming Shuai, Jinbo Gao, Kaixiong Tao, Guobin Wang, Hang Li
BACKGROUND: Recent studies have shown that interferon-γ (IFN-γ)-induced galectin-9 expression in Kupffer cells plays an essential role in modulatingthe microenvironment of hepatitis-associated hepatocellular carcinoma (HCC). However, whether or not IFN-γ induces galectin-9 expression in HCC cells, its biological role and regulatory mechanism in HCC development and progression are poorly defined. METHODS: Quantitative PCR and western blotting analysis were used to detect galectin-9 and EZH2 levels in HCC cell lines stimulated with IFN-γ...
January 9, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29312470/combined-inhibition-of-bet-proteins-and-class-i-hdacs-synergistically-induces-apoptosis-in-urothelial-carcinoma-cell-lines
#19
Alexander S Hölscher, Wolfgang A Schulz, Maria Pinkerneil, Günter Niegisch, Michèle J Hoffmann
Background: New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29290968/inhibition-of-ezh2-triggers-the-tumor-suppressive-mir-29b-network-in-multiple-myeloma
#20
Maria Angelica Stamato, Giada Juli, Enrica Romeo, Domenica Ronchetti, Mariamena Arbitrio, Daniele Caracciolo, Antonino Neri, Pierosandro Tagliaferri, Pierfrancesco Tassone, Nicola Amodio
Downregulation of tumor suppressor (TS) microRNAs (miRNAs) commonly occurs in human cancer, including multiple myeloma (MM). We previously demonstrated that miR-29b is a relevant TS miRNA, whose expression in MM cells is inhibited by HDAC4-dependent deacetylation. Here, we provide novel insights into epigenetic mechanisms suppressing miR-29b in MM. In MM patient-derived plasma cells, we found inverse correlation between miR-29b and EZH2 mRNA expression. Both siRNAs and pharmacologic inhibitors of EZH2 led to miR-29b upregulation, and this effect was ascribed to reduced H3K27-trimethylation (H3K27me3) of miR-29a/b-1 promoter regions...
December 5, 2017: Oncotarget
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