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      Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis

      1 , 2 , 1 , 1 , 3 , 1 , 1 , 1 , 1 , 4 , 5 , 1 , 5 , 6 , 4 , 5 , 1 , 1 ,

      Cellular and Molecular Gastroenterology and Hepatology

      Elsevier

      EZH2, Liver Fibrosis, Epigenetics, Histone Modifications, BDL, bile duct ligation, CCL4, carbon tetrachloride, ChIP, chromatin immunoprecipitation, CTGF, connective tissue growth factor, DKK1, Dickkopf-1, ECM, extracellular matrix, EZH2, enhancer of zeste homologue 2, FBS, fetal bovine serum, FDR, false discovery rate, H3K27me3, trimethylation of histone 3 at lysine 27, HCC, hepatocellular carcinoma, HMT, histone methyltransferase, HSC, hepatic stellate cell, IP, intraperitoneally, IPA, Ingenuity Pathway Analysis, logFC, logarithmic fold change, mRNA, messenger RNA, PCR, polymerase chain reaction, PDGF, platelet-derived growth factor, siRNA, small interfering RNA, α-SMA, α-smooth muscle actin, TGF-β, transforming growth factor β, VEGFA, vascular endothelial growth factor A, WT, wild type

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          Abstract

          Background & Aims

          Transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts is a key event in the pathogenesis of liver fibrosis. Transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF) are canonical HSC activators after liver injury. The aim of this study was to analyze the epigenetic modulators that differentially control TGF-β and PDGF signaling pathways.

          Methods

          We performed a transcriptomic comparison of HSCs treated with TGF-β or PDGF-BB using RNA sequencing. Among the targets that distinguish these 2 pathways, we focused on the histone methyltransferase class of epigenetic modulators.

          Results

          Enhancer of zeste homolog 2 (EZH2) was expressed differentially, showing significant up-regulation in HSCs activated with TGF-β but not with PDGF-BB. Indeed, EZH2 inhibition using either a pharmacologic (GSK-503) or a genetic (small interfering RNA) approach caused a significant attenuation of TGF-β–induced fibronectin, collagen 1α1, and α-smooth muscle actin, both at messenger RNA and protein levels. Conversely, adenoviral overexpression of EZH2 in HSCs resulted in a significant stimulation of fibronectin protein and messenger RNA levels in TGF-β–treated cells. Finally, we conducted in vivo experiments with mice chronically treated with carbon tetrachloride or bile duct ligation. Administration of GSK-503 to mice receiving either carbon tetrachloride or bile duct ligation led to attenuated fibrosis as assessed by Trichrome and Sirius red stains, hydroxyproline, and α-smooth muscle actin/collagen protein assays.

          Conclusions

          TGF-β and PDGF share redundant and distinct transcriptomic targets, with the former predominating in HSC activation. The EZH2 histone methyltransferase is preferentially involved in the TGF-β as opposed to the PDGF signaling pathway. Inhibition of EZH2 attenuates fibrogenic gene transcription in TGF-β–treated HSCs and reduces liver fibrosis in vivo. The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE119606 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE119606)

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          Most cited references 36

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          Polycomb group protein ezh2 controls actin polymerization and cell signaling.

          Polycomb group protein Ezh2, one of the key regulators of development in organisms from flies to mice, exerts its epigenetic function through regulation of histone methylation. Here, we report the existence of the cytosolic Ezh2-containing methyltransferase complex and tie the function of this complex to regulation of actin polymerization in various cell types. Genetic evidence supports the essential role of cytosolic Ezh2 in actin polymerization-dependent processes such as antigen receptor signaling in T cells and PDGF-induced dorsal circular ruffle formation in fibroblasts. Revealed function of Ezh2 points to a broader usage of lysine methylation in regulation of both nuclear and extra-nuclear signaling processes.
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            The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors.

            Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumorigenesis in vivo remains poor, in particular in metastasizing solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress either melanoma growth or metastasis in vivo, revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanoma progression, which makes EZH2 a promising target for novel melanoma therapies.
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              Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype.

              Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodeling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. Long-term adaptation to a hypoxic insult is likely to require significant modification of chromatin structure in order to maintain the fibrotic phenotype. Epigenetic changes may play an important role in modulating hypoxia-induced fibrosis within the heart. Therefore, the aim of the study was to investigate the potential pro-fibrotic impact of hypoxia on cardiac fibroblasts and determine whether alterations in DNA methylation could play a role in this process. This study found that within human cardiac tissue, the degree of hypoxia was associated with increased expression of collagen 1 and alpha-smooth muscle actin (ASMA). In addition, human cardiac fibroblast cells exposed to prolonged 1% hypoxia resulted in a pro-fibrotic state. These hypoxia-induced pro-fibrotic changes were associated with global DNA hypermethylation and increased expression of the DNA methyltransferase (DNMT) enzymes DNMT1 and DNMT3B. Expression of these methylating enzymes was shown to be regulated by hypoxia-inducible factor (HIF)-1α. Using siRNA to block DNMT3B expression significantly reduced collagen 1 and ASMA expression. In addition, application of the DNMT inhibitor 5-aza-2'-deoxycytidine suppressed the pro-fibrotic effects of TGFβ. Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu. Targeting up-regulated expression of DNMTs in ischemic heart disease may prove to be a valuable therapeutic approach.
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                Author and article information

                Contributors
                Journal
                Cell Mol Gastroenterol Hepatol
                Cell Mol Gastroenterol Hepatol
                Cellular and Molecular Gastroenterology and Hepatology
                Elsevier
                2352-345X
                2019
                15 September 2018
                : 7
                : 1
                : 197-209
                Affiliations
                [1 ]Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
                [2 ]Division of Gastroenterology and Hepatology, Ramón y Cajal University Hospital, Madrid, Spain
                [3 ]Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
                [4 ]Genomics and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, Wisconsin
                [5 ]Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
                [6 ]Service Maladie de l'Appareil Digestif, INSERM U995 Université Lille 2, Centre Hospitalier Régionale Universitaire (CHRU) de Lille, France
                Author notes
                [] Correspondence Address correspondence to: Vijay H. Shah, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. fax: (507) 255-6318. shah.vijay@ 123456mayo.edu
                Article
                S2352-345X(18)30127-9
                10.1016/j.jcmgh.2018.09.005
                6282644
                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                Categories
                Original Research

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