EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis

Abstract

// Kei Ihira 1, * , Peixin Dong 2, * , Ying Xiong 3, * , Hidemichi Watari 1 , Yosuke Konno 1 , Sharon JB Hanley 2 , Masayuki Noguchi 4 , Noriyuki Hirata 4 , Futoshi Suizu 4 , Takahiro Yamada 2 , Masataka Kudo 1 , Noriaki Sakuragi 1, 2 1 Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan 2 Department of Women’s Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan 3 Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China 4 Division of Cancer Biology, Institute for Genetic Medicine Hokkaido University N15, W7, Sapporo 0608638, Japan * These authors contributed equally to this work Correspondence to: Peixin Dong, email: dpx1cn@gmail.com Hidemichi Watari, email: watarih@med.hokudai.ac.jp Noriaki Sakuragi, email: sakuragi@med.hokudai.ac.jp Keywords: EZH2, GSK343, miR-361, endometrial cancer, 5-AZA-CdR Received: July 20, 2016      Accepted: January 03, 2017      Published: January 10, 2017 ABSTRACT EZH2 inhibition and reactivation of tumor suppressor microRNAs (miRNAs) represent attractive anti-cancer therapeutic strategies. We found that EZH2-suppressed let 7b and miR-361, two likely tumor suppressors, inhibited endometrial cancer (EC) cell proliferation and invasion, and abrogated cancer stem cell-like properties. In EC cells, EZH2 induced and functioned together with YY1 to epigenetically suppress miR-361, which upregulated Twist, a direct target of miR-361. Treating EC cells with GSK343, a specific EZH2 inhibitor, mimicked the effects of siRNA-mediated EZH2 knockdown, upregulating miR-361 and downregulating Twist expression. Combining GSK343 with 5 AZA-2’-deoxycytidine synergistically suppressed cell proliferation and invasion in vitro , and decreased tumor size and weight in EC cell xenografted mice. Quantitative real-time PCR analysis of 24 primary EC tissues showed that lower let-7b and miR-361 levels were associated with worse patient outcomes. These results were validated in a larger EC patient dataset from The Cancer Genome Atlas. Our findings suggest that EZH2 drives EC progression by regulating miR-361/Twist signaling, and support EZH2 inhibition as a promising anti-EC therapeutic strategy.