HDAC4 stimulates MRTF-A expression and drives fibrogenesis in hepatic stellate cells by targeting miR-206

// Xinrui Han 1 , Chenzhi Hao 2 , Luyang Li 2 , Jianfei Li 2 , Mingming Fang 2 , Yuanlin Zheng 1 , Jun Lu 1 , Ping Li 3 and Yong Xu 2 1 Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China 2 Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China 3 Department of Gastroenterology, 2nd Affiliated Hospital to Nanjing Medical University, Nanjing, China Correspondence to: Jun Lu, email: lu-jun75@163.com Ping Li, email: pinglinjmu@gmail.com Yong Xu, email: yjxu@njmu.edu.cn Keywords: HDAC4, hepatic stellate cell, liver fibrosis, MRTF-A, miRNA Received: February 06, 2017 Accepted: April 26, 2017 Published: May 10, 2017 ABSTRACT 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.