Research Papers: Pathology:

Resveratrol suppresses myofibroblast activity of human buccal mucosal fibroblasts through the epigenetic inhibition of ZEB1 expression

Yu-Chao Chang, Cheng-Wei Lin, Cheng-Chia Yu, Bing-Yen Wang, Yu-Hao Huang, Yang-Chih Hsieh, Yu-Liang Kuo and Wen-Wei Chang _

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Oncotarget. 2016; 7:12137-12149. https://doi.org/10.18632/oncotarget.7763

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Yu-Chao Chang1,2,*, Cheng-Wei Lin3,*, Cheng-Chia Yu1,2,4, Bing-Yen Wang5,6,7, Yu-Hao Huang3, Yang-Chih Hsieh3, Yu-Liang Kuo8,9 and Wen-Wei Chang3,10

1 School of Dentistry, Chung Shan Medical University, Taichung, Taiwan

2 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan

3 School of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan

4 Institute of Oral Science, Chung Shan Medical University, Taichung, Taiwan

5 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan

6 Division of Throacic Surgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan

7 School of Medicine, National Yang-Ming University, Taipei, Taiwan

8 School of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan

9 Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung, Taiwan

10 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

* These authors have contributed equally to this work

Correspondence to:

Wen-Wei Chang, email:

Keywords: resveratrol, oral submucous fibrosis, ZEB1, EZH2, H3K27me3, Pathology Section

Received: July 16, 2015 Accepted: February 18, 2016 Published: February 26, 2016


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.

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