title: Resveratrol suppresses myofibroblast activity of human buccal mucosal fibroblasts through the epigenetic inhibition of ZEB1 expression.
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.
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.|Institute of Oral Science, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Division of Throacic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Bing-Yen
authors.initials: BY
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yu-Hao
authors.initials: YH
authors.lastname: Huang
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yang-Chih
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Kuo
authors.affiliation: School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
mesh_terms: D000071221:Enhancer of Zeste Homolog 2 Protein / Q000096:biosynthesis; D057890:Epigenomics; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009061:Mouth Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism; D009914:Oral Submucous Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D013267:Stilbenes; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D000077185:Resveratrol
keywords: EZH2; H3K27me3; Pathology Section; ZEB1; oral submucous fibrosis; resveratrol