Research Papers:
EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis
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Abstract
Kei Ihira1,*, Peixin Dong2,*, Ying Xiong3,*, Hidemichi Watari1, Yosuke Konno1, Sharon JB Hanley2, Masayuki Noguchi4, Noriyuki Hirata4, Futoshi Suizu4, Takahiro Yamada2, Masataka Kudo1, Noriaki Sakuragi1,2
1Department of Gynecology, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan
2Department of Women’s Health Educational System, Hokkaido University School of Medicine, Hokkaido University, Sapporo 0608638, Japan
3Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, P. R. China
4Division 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: [email protected]
Hidemichi Watari, email: [email protected]
Noriaki Sakuragi, email: [email protected]
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.
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PII: 14586