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.

Aberrant SSEA-4 upregulation mediates myofibroblast activity to promote pre-cancerous oral submucous fibrosis

“…Arecoline, the major areca nut alkaloid, could activate the transdifferentiation of oral keratinocytes into myofibroblasts8. Previously, we have also identified that the treatment of arecoline could induce myofibroblasts activities in human normal buccal mucosal fibroblasts (BMFs)91011, supporting the crucial roles of myofibroblasts transdifferentiation during the pathogenesis of OSF.…”

Sirtuin 1 and oral cancer (Review)

“…SIRT1, sirtuin 1; TGF-β, transforming growth factor beta; OSF, oral submucous fibrosis. transcriptional suppression of TGF-β-mediated downstream targets in fibroblasts and to prevent malignant transformation (44). Based on these observations, SIRT1 may have the ability to prevent malignant transformation, invasion, and metastasis.…”

Resveratrol (3,5,4′-trihydroxystilbene) and its properties in oral diseases

“…Moderate-to-severe OSF is irreversible and current treatment strategies include injections or topical application of steroids, oral subministration of lycopene (16 mg daily) and pentoxyfilline (400 mg 3 times daily) (16,118,119). A previous study demonstrated that RSV epigenetically inhibits Zinc finger E-Box binding homeobox 1 expression to suppress the myofibroblast activity of fibrotic buccal mucosal fibroblasts, and may serve as a dietary supplement for OSF patients (120).…”