DZNep, an inhibitor of the histone methyltransferase EZH2, suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 pathway

PeerJ

article

Rongrong Ding¹  Jianming Zheng¹  Ning Li¹  Qi Cheng¹  Mengqi Zhu¹  Yanbing Wang²  Xinlan Zhou²  Zhanqing Zhang²  Guangfeng Shi¹ 

[1] Infectious Diseases, Huashan Hospital, Fudan University;Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University

关键词: Hepatic fibrosis;    DZNep;    TGF-β1;    EZH2;    miR-199a-5p;    SOCS7;   

DOI  :  10.7717/peerj.11374

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

BackgroundHepatic fibrosis is a common response to chronic liver injury. Recently, the role of DZNep (a histone methyltransferase EZH2 inhibitor) in repressing pulmonary and renal fibrosis was verified. However, the potential effect of DZNep on hepatic fibrosis has not been elucidated.MethodsThe hepatic fibrosis model was established in rats treated with CCl4 and in hepatic stellate cells (HSCs) treated with TGF-β1. The liver tissues were stained with H&E and Masson’s trichrome. The expression of EZH2, SOCS7, collagen I, αSMA mRNA and miR-199-5p was assessed using qPCR, immunohistochemical or western blot analysis. A dual-luciferase reporter assay was carried out to validate the regulatory relationship of miR-199a-5p with SOCS7.ResultsThe EZH2 level was increased in CCl4-treated rats and in TGF-β1-treated HSCs, whereas DZNep treatment significantly inhibited EZH2 expression. DZNep repressed hepatic fibrosis in vivo and in vitro, as evidenced by the decrease of hepatic fibrosis markers (α-SMA and Collagen I). Moreover, miR-199a-5p expression was repressed by DZNep in TGF-β1-activated HSCs. Notably, downregulation of miR-199a-5p decreased TGF-β1-induced expression of fibrosis markers. SOCS7 was identified as a direct target of miR-199a-5p. The expression of SOCS7 was decreased in TGF-β1-activated HSCs, but DZNep treatment restore d SOCS7 expression. More importantly, SOCS7 knockdown decreased the effect of DZNep on collagen I and α SMA expression in TGF-β1-activated HSCs.ConclusionsDZNep suppresses hepatic fibrosis through regulating miR-199a-5p/SOCS7 axis, suggesting that DZNep may represent a novel treatment for fibrosis.

【 授权许可】

CC BY