EZH2-mediated repression of Dkk1 promotes hepatic stellate cell activation and hepatic fibrosis.
EZH2, a histone H3 lysine-27-specific methyltransferase, is involved in diverse physiological and pathological processes including cell proliferation and differentiation. However, the role of EZH2 in liver fibrosis is largely unknown. In this study, it was identified that EZH2 promoted Wnt pathway-stimulated fibroblasts in vitro and in vivo by repressing Dkk-1, which is a Wnt pathway antagonist. The expression of EZH2 was increased in CCl4-induced rat liver and primary HSCs as well as TGF-β1-treated HSC-T6, whereas the expression of Dkk1 was reduced. Silencing of EZH2 prevented TGF-β1-induced proliferation of HSC-T6 cells and the expression of α-SMA. In addition, knockdown of Dkk1 promoted TGF-β1-induced activation of HSCs. Moreover, silencing of EZH2 could restore the repression of Dkk-1 through trimethylation of H3K27me3 in TGF-β1-treated HSC-T6 cells. Interestingly, inhibition of EZH2 had almost no effect on the activation of HSC when Dkk1 was silenced. Collectively, EZH2-mediated repression of Dkk1 promotes the activation of Wnt/β-catenin pathway, which is an essential event for HSC activation.
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Yang
Y
Yang
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.|Department of Pharmacy, Anhui No. 2 Province People's Hospital, Hefei, China.
Xiao-Xia
XX
Chen
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Wan-Xia
WX
Li
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Xiao-Qin
XQ
Wu
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Cheng
C
Huang
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Juan
J
Xie
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Yu-Xin
YX
Zhao
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Xiao-Ming
XM
Meng
The key of Laboratory Precision Medicine for Severe Autoimmune Diseases of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China.|The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.|Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Jun
0000-0003-4668-4105
J
Li
D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
C531384:Dkk1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride; C578253:EZH2 protein, rat; D000071221:Enhancer of Zeste Homolog 2 Protein
Dickkopf1; Hepatic fibrosis; Wnt/β-catenin pathway; enhancer of zeste homologue 2; histone methylation