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EZH2-mediated repression of Dkk1 promotes hepatic stellate cell activation and hepatic fibrosis.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2017 Oct; Vol. 21 (10), pp. 2317-2328. Date of Electronic Publication: 2017 Mar 23. - Publication Year :
- 2017
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Abstract
- 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 CCl <subscript>4</subscript> -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.<br /> (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Subjects :
- Animals
Carbon Tetrachloride
Cell Line
Cell Proliferation drug effects
Cell Proliferation genetics
Cells, Cultured
Enhancer of Zeste Homolog 2 Protein genetics
Gene Expression Regulation
Hepatic Stellate Cells drug effects
Intercellular Signaling Peptides and Proteins genetics
Liver Cirrhosis chemically induced
Liver Cirrhosis genetics
RNA Interference
Rats, Sprague-Dawley
Transforming Growth Factor beta1 pharmacology
Wnt Signaling Pathway drug effects
Wnt Signaling Pathway genetics
Enhancer of Zeste Homolog 2 Protein metabolism
Hepatic Stellate Cells metabolism
Intercellular Signaling Peptides and Proteins metabolism
Liver Cirrhosis metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 21
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28332284
- Full Text :
- https://doi.org/10.1111/jcmm.13153