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Histone deacetylase inhibition suppresses the transforming growth factor β1–induced epithelial‐to‐mesenchymal transition in hepatocytes
Author(s) -
Kaimori Aki,
Potter James J.,
Choti Michael,
Ding Zhen,
Mezey Esteban,
Koteish Ayman A.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23765
Subject(s) - trichostatin a , histone deacetylase , epithelial–mesenchymal transition , histone deacetylase inhibitor , cancer research , transforming growth factor , chemistry , biology , microbiology and biotechnology , histone , downregulation and upregulation , biochemistry , gene
Transforming growth factor β1 (TGFβ1) plays a crucial role in the induction of the epithelial‐to‐mesenchymal transition (EMT) in hepatocytes, which contributes to the pathogenesis of liver fibrosis. The inhibition of the TGFβ1 cascade suppresses EMT and the resultant fibrosis. In this study, we focus on EMT‐induced fibrosis in hepatocytes and the epigenetic regulation of the type I collagen gene. Histone acetylation is an important, major epigenetic mechanism that modulates gene transcription. We evaluated the epigenetic regulation of type I collagen in alpha mouse liver 12 hepatocytes (an untransformed mouse cell line) that had undergone EMT after treatment with TGFβ1. The histone deacetylase inhibitor trichostatin A (TSA) inhibited EMT; this was reflected by the preservation of epithelial markers and function (E‐cadherin and albumin). Fibrosis, the ultimate outcome of EMT, was abolished by TSA; this was indicated by the inhibition of type I collagen deposition. TSA exerted its anti‐EMT effects by deactivating the mothers against decapentaplegic homolog 3 (Smad3)/Smad4 transcription complex and by interfering with p300, a coactivator of the type I collagen promoter, and preventing its binding to Smad3. TSA also restored Friend leukemia virus integration 1, an inhibitor of the type I collagen gene. TGFβ1‐induced EMT and its inhibition by TSA were replicated in human primary hepatocytes. Conclusion: Histone deacetylase inhibition abrogates TGFβ1‐induced EMT in hepatocytes and reverses EMT‐induced fibrosis by epigenetic modulation of type I collagen. (H EPATOLOGY 2010)