Interplay of DNA methyltransferase 1 and EZH2 through inactivation of Stat3 contributes to β-elemene-inhibited growth of nasopharyngeal carcinoma cells

Abstract

Abstract β-elemene, a compound extracted from Curcuma wenyujin plant, exhibits anticancer activity in many cancer types. However, the detailed mechanism by which β-elemene inhibits growth of nasopharyngeal carcinoma (NPC) cells remains unknown. We showed that β-elemene reduced phosphorylation of signal transducer and activator of transcription 3 (Stat3), and protein expressions of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2). Exogenously expressed Stat3 antagonized the effect of β-elemene on DNMT1 and EZH2 expressions. Furthermore, overexpressions of DNMT1 and EZH2 reversed the effect of β-elemene on phosphorylation of Stat3 and cell growth inhibition. Intriguingly, exogenously expressed DNMT1 overcame β-elemene-inhibited EZH2 protein expression and promoter activity. On the contrary, silencing of EZH2 and DNMT1 genes feedback strengthened the effect of β-elemene on phosphorylation of Stat3. Consistent with this, β-elemene inhibited tumor growth, phosphorylation of Stat3, expressions of DNMT1 and EZH2 in a mouse xenograft model. Collectively, this study shows that β-elemene inhibits NPC cell growth via inactivation of Stat3, and reduces DNMT1 and EZH2 expressions. The interplay of DNMT1 and EZH2, and the mutual regulations among Stat3, EZH2 and DNMT1 contribute to the overall responses of β-elemene. This study uncovers a novel mechanism by which β-elemene inhibits growth of NPC cells.