Details

Autor(en) / Beteiligte

• Kaimori, Aki
• Potter, James J
• Choti, Michael
• Ding, Zhen
• Mezey, Esteban
• Koteish, Ayman A

Titel

Histone deacetylase inhibition suppresses the transforming growth factor beta 1-induced epithelial-to-mesenchymal transition in hepatocytes

Ist Teil von

• Hepatology (Baltimore, Md.), 2010-09, Vol.52 (3), p.1033-1045

Erscheinungsjahr

2010

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Transforming growth factor beta 1 (TGF beta 1) 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 TGF beta 1 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 TGF beta 1. 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. TGF beta 1-induced EMT and its inhibition by TSA were replicated in human primary hepatocytes. Conclusion: Histone deacetylase inhibition abrogates TGF beta 1-induced EMT in hepatocytes and reverses EMT-induced fibrosis by epigenetic modulation of type I collagen. (HEPATOLOGY 2010)