2024-03-28T19:34:40Zhttps://eprints.lib.hokudai.ac.jp/dspace-oai/requestoai:eprints.lib.hokudai.ac.jp:2115/645622022-11-17T02:08:08Zhdl_2115_20040hdl_2115_121EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axisIhira, KeiDong, PeixinXiong, YingWatari, HidemichiKonno, YosukeHanley, Sharon JBNoguchi, MasayukiHirata, NoriyukiSuizu, FutoshiYamada, TakahiroKudo, MasatakaSakuragi, NoriakiEZH2GSK343miR-361endometrial cancer5-AZA-CdR490EZH2 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.Impact JournalsJournal Articleapplication/pdfhttp://hdl.handle.net/2115/64562https://eprints.lib.hokudai.ac.jp/dspace/bitstream/2115/64562/1/14586-216712-3-PB.pdf1949-2553Oncotarget8813509135202017-02-21enginfo:doi/10.18632/oncotarget.14586http://creativecommons.org/licenses/by/3.0/publisher