Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma

Abstract

Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of vimentin. How Twist1 regulates this expression remains unclear. Here, we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and to selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 <i>in vitro</i> and in patient-derived xenograft and diethylnitrosamine-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circular RNA (circRNA)-based diagnostic and therapeutic strategies.<b>Significance:</b> A circRNA-based mechanism drives Twist1-mediated regulation of vimentin during EMT and provides potential therapeutic targets for treatment of HCC.<b>Graphical Abstract:</b> http://cancerres.aacrjournals.org/content/canres/78/15/4150/F1.large.jpg <i>Cancer Res; 78(15); 4150-62. ©2018 AACR</i>.