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Resveratrol suppresses myofibroblast activity of human buccal mucosal fibroblasts through the epigenetic inhibition of ZEB1 expression.
- Source :
-
Oncotarget [Oncotarget] 2016 Mar 15; Vol. 7 (11), pp. 12137-49. - Publication Year :
- 2016
-
Abstract
- Oral submucous fibrosis (OSF) is a precancerous condition of the oral mucosa without specific therapeutic drugs. We previously demonstrated that the zinc finger E-box binding homeobox 1 (ZEB1) plays a pathogenic role in the induction of the myofibroblast activity of buccal mucosal fibroblasts (BMFs) and contributes to the pathogenesis of OSF. Resveratrol is a natural polyphenolic flavonoid with anti-fibrosis activity in various tissues and has the capability to inhibit ZEB1 in oral cancer cells. We examined the effect of resveratrol on the myofibroblast activity of human primary fibrotic BMFs (fBMFs) derived from OSF tissues. With the collagen contraction assay, resveratrol displayed anti-myofibroblast activity in three fBMF lines. Resveratrol also inhibited the expression of fibrogenic genes at the mRNA and protein levels in a dose- and time-dependent manner. The downregulation of ZEB1 in fBMFs by resveratrol was mediated by epigenetic mechanisms, such as the upregulated expression of miR-200c and the enhancer of zeste homolog 2 (EZH2), as well as the trimethylated lysine 27 of histone H3 (H3K27me3). Resveratrol also increased the binding of H3K27me3 to the ZEB1 promoter. The knockdown of EZH2 in fBMFs caused the upregulation of ZEB1 and suppressed the inhibitory effect of resveratrol. Furthermore, the reversed expression pattern between EZH2 and ZEB1 was observed in 6/8 OSF tissues with twofold upregulation of ZEB1 expression compared with the adjacent normal mucosa. In conclusion, our data suggest that resveratrol epigenetically inhibits ZEB1 expression to suppress the myofibroblast activity of fBMFs and may serve as a dietary supplement for OSF patients.
- Subjects :
- Enhancer of Zeste Homolog 2 Protein biosynthesis
Epigenomics
Fibroblasts metabolism
Humans
Mouth Mucosa metabolism
Mouth Mucosa pathology
Mouth Neoplasms pathology
Myofibroblasts metabolism
Oral Submucous Fibrosis metabolism
Precancerous Conditions metabolism
Precancerous Conditions pathology
Resveratrol
Zinc Finger E-box-Binding Homeobox 1 biosynthesis
Zinc Finger E-box-Binding Homeobox 1 genetics
Fibroblasts drug effects
Mouth Mucosa drug effects
Mouth Neoplasms drug therapy
Myofibroblasts drug effects
Oral Submucous Fibrosis drug therapy
Precancerous Conditions drug therapy
Stilbenes pharmacology
Zinc Finger E-box-Binding Homeobox 1 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26934322
- Full Text :
- https://doi.org/10.18632/oncotarget.7763