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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:30539787", "kind": "science-record", "revision": 8, "content_hash": "sha256:daa17524d7c2b8fd5f1e38ddda17106b7f4a980ee3eaaedfa736911f245f946a", "created_at": "2026-11-01T15:40:39Z", "updated_at": "2026-11-01T22:43:39Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Enhancer of Zeste Homologue 2 Inhibition Attenuates TGF-β Dependent Hepatic Stellate Cell Activation and Liver Fibrosis.", "doi": "10.1016/j.jcmgh.2018.09.005", "pmid": "30539787", "authors": ["Rosa Martin-Mateos", "Thiago M De Assuncao", "Juan Pablo Arab", "Nidhi Jalan-Sakrikar", "Usman Yaqoob", "Thomas Greuter", "Vikas K Verma", "Angela J Mathison", "Sheng Cao", "Gwen Lomberk", "Philippe Mathurin", "Raul Urrutia", "Robert C Huebert", "Vijay H Shah"], "journal": "Cellular and molecular gastroenterology and hepatology", "year": 2019, "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.\nMETHODS: 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.\nRESULTS: 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.\nCONCLUSIONS: 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).", "claims": [{"id": "claim-method", "statement": "Analysis of variance with Bonferroni post-test, nonparametric 2-tailed t test (Mann–Whitney), or paired t test for cell culture experiments were used to assess the statistical significance between groups as appropriate with GraphPad Prism 5 software (GraphPad Software, Inc, La Jolla, CA).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30539787", "locator": "sections[26] \"Statistical Analysis\" paragraph 2", "quote": "Analysis of variance with Bonferroni post-test, nonparametric 2-tailed t test (Mann–Whitney), or paired t test for cell culture experiments were used to assess the statistical significance between groups as appropriate with GraphPad Prism 5 software (GraphPad Software, Inc, La Jolla, CA)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "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)", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:30539787", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "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)"}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:30539787"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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