Identification of a TGF-β-miR-195 positive feedback loop in hepatocytes and its deregulation in hepatoma cells

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Ruizhi WangShi-Mei Zhuang

Abstract

Resistance to TGF-β-induced growth repression is prevalent in various cancer cells, but the underlying mechanisms remain unclear. In this study, we showed that activation of TGF-β signaling caused Sma- and Mad-related family (Smad) 2 and Smad3 to bind directly to the promoter region of miR-195, and then activated miR-195 transcription in normal hepatocytes. Conversely, miR-195 inhibited the expression of Smad7 by binding to its 3'-UTR, thereby strengthening TGF-β-Smad signaling. These data identify a novel TGF-β-miR-195 positive regulatory circuitry in normal hepatocytes. Further investigation revealed that HDAC1, a histone deacetylase that was abnormally overexpressed in hepatocellular carcinoma, could bind to the miR-195 promoter via Smad3 and cause hypoacetylation in the histones associated with the miR-195 promoter in hepatoma cells. This resulted in transcriptional repression of miR-195 and, subsequently, disruption of the TGF-β-miR-195 regulatory loop and evasion of TGF-β-mediated growth inhibition. Moreover, silencing HDAC1 in hepatoma cells restored TGF-β-mediated growth suppression, but this effect was attenuated if miR-195 expression decreased. These findings suggest that HDAC1-induced miR-195 down-regulation is an im...Continue Reading

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Citations

Oct 17, 2019·Cells·Shuo TuXiaohua Yan
Jul 23, 2020·Frontiers in Oncology·Yuehui LiangFang Xiao
Oct 22, 2020·Critical Reviews in Biochemistry and Molecular Biology·Charlotte de Ceuninck van CapellePeter Ten Dijke
Nov 25, 2020·Archives of Biochemistry and Biophysics·Fang YuanYin-Xiong Li

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