HDAC4 stimulates MRTF-A expression and drives fibrogenesis in hepatic stellate cells by targeting miR-206
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Xinrui Han1, Chenzhi Hao2, Luyang Li2, Jianfei Li2, Mingming Fang2, Yuanlin Zheng1, Jun Lu1, Ping Li3 and Yong Xu2
1Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China
2Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China
3Department of Gastroenterology, 2nd Affiliated Hospital to Nanjing Medical University, Nanjing, China
Jun Lu, email: [email protected]
Ping Li, email: [email protected]
Yong Xu, email: [email protected]
Keywords: HDAC4, hepatic stellate cell, liver fibrosis, MRTF-A, miRNA
Received: February 06, 2017 Accepted: April 26, 2017 Published: May 10, 2017
Activation of hepatic stellate cells (HSCs) is a hallmark event during liver fibrogenesis. We have previously shown that the transcriptional modulator MRTF-A contributes to liver fibrosis by programming epigenetic activation of HSCs. In the present study we investigated the mechanism whereby MRTF-A expression is regulated in this process. We report here that MRTF-A protein levels, but not mRNA levels, were up-regulated in vivo in the livers of mice induced to develop hepatic fibrosis. Pro-fibrogenic stimuli (TGF-β and PDGF-BB) also activated MRTF-A expression post-transcriptionally in vitro in cultured HSCs. miR-206 bound to the 3′-UTR of MRTF-A presumably to inhibit translation. miR-206 levels were down-regulated in response to pro-fibrogenic stimuli in vivo and in vitro allowing MRTF-A proteins to accumulate. Mechanistically, histone deacetylase 4 (HDAC4) was induced by pro-fibrogenic stimuli and recruited to the miR-206 promoter to repress miR-206 transcription. HDAC4 stimulated MRTF-A expression and drove fibrogenesis in HSCs in a miR-206 dependent manner. Therefore, our data reveal an HDAC4-miR-206-MRTF-A axis that can play a potentially important role in HSC activation and liver fibrosis.
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