EZH2-mediated inhibition of KLF14 expression promotes HSCs activation and liver fibrosis by downregulating PPARγ

被引：25

作者：

Du, Zhipeng ^{[1
]}

Liu, Mei ^{[1
]}

Wang, Zhihui ^{[1
]}

Lin, Zhuoying ^{[1
]}

Feng, Yangyang ^{[1
]}

Tian, Dean ^{[1
]}

Xia, Limin ^{[1
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Hosp, Hubei Key Lab Hepatopancreatobiliary Dis, Dept Gastroenterol,Inst Liver & Gastrointestinal, Wuhan 430030, Hubei, Peoples R China

来源：

CELL PROLIFERATION | 2021年 / 54卷 / 07期

基金：

中国国家自然科学基金;

关键词：

enhancer of zeste homolog 2; hepatic stellate cell; krü ppel‐ like factor 14; liver fibrosis; peroxisome proliferator‐ activated receptor γ HEPATIC STELLATE CELLS; DNA METHYLATION; MECHANISMS; POLYCOMB; CURCUMIN; LIGANDS; GROWTH; LOCI;

D O I：

10.1111/cpr.13072

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Objectives Induction of deactivation and apoptosis of hepatic stellate cells (HSCs) are principal therapeutic strategies for liver fibrosis. Kruppel-like factor 14 (KLF14) regulates various biological processes, however, roles, mechanisms and implications of KLF14 in liver fibrosis are unknown. Materials and Methods KLF14 expression was detected in human, rat and mouse fibrotic models, and its effects on HSCs were assessed. Chromatin immunoprecipitation assays were utilized to investigate the binding of KLF14 to peroxisome proliferator-activated receptor gamma (PPAR gamma) promoter, and the binding of enhancer of zeste homolog 2 (EZH2) to KLF14 promoter. In vivo, KLF14-overexpressing adenovirus was injected via tail vein to thioacetamide (TAA)-treated rats to investigate the role of KLF14 in liver fibrosis progression. EZH2 inhibitor EPZ-6438 was utilized to treat TAA-induced rat liver fibrosis. Results KLF14 expression was remarkably decreased in human, rat and mouse fibrotic liver tissues. Overexpression of KLF14 increased LD accumulation, inhibited HSCs activation, proliferation, migration and induced G2/M arrest and apoptosis. Mechanistically, KLF14 transactivated PPAR gamma promoter activity. Inhibition of PPAR gamma blocked the suppressive role of KLF14 overexpression in HSCs. Downregulation of KLF14 in activated HSCs was mediated by EZH2-regulated histone H3 lysine 27 trimethylation. Adenovirus-mediated KLF14 overexpression ameliorated TAA-induced rat liver fibrosis in PPAR gamma-dependent manner. Furthermore, EPZ-6438 dramatically alleviated TAA-induced rat liver fibrosis. Importantly, KLF14 expression was decreased in human with liver fibrosis, which was significantly correlated with EZH2 upregulation and PPAR gamma downregulation. Conclusions KLF14 exerts a critical anti-fibrotic role in liver fibrosis, and targeting the EZH2/KLF14/PPAR gamma axis might be a novel therapeutic strategy for liver fibrosis.

引用

页数：17

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