RRC ID 65117
著者 Ihira K, Dong P, Xiong Y, Watari H, Konno Y, Hanley SJ, Noguchi M, Hirata N, Suizu F, Yamada T, Kudo M, Sakuragi N.
タイトル EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis.
ジャーナル Oncotarget
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.
巻・号 8(8)
ページ 13509-13520
公開日 2017-2-21
DOI 10.18632/oncotarget.14586
PII 14586
PMID 28088786
PMC PMC5355116
MeSH Animals Cell Line, Tumor Disease Progression Endometrial Neoplasms / drug therapy* Endometrial Neoplasms / genetics Endometrial Neoplasms / metabolism Endometrial Neoplasms / pathology Enhancer of Zeste Homolog 2 Protein / antagonists & inhibitors* Enhancer of Zeste Homolog 2 Protein / genetics Enhancer of Zeste Homolog 2 Protein / metabolism Enzyme Inhibitors / pharmacology* Female Humans Indazoles / pharmacology* Mice Mice, Inbred BALB C MicroRNAs / metabolism* Nuclear Proteins / metabolism* Pyridones / pharmacology* Transfection Twist-Related Protein 1 / metabolism* Xenograft Model Antitumor Assays
IF 5.168
リソース情報
ヒト・動物細胞 HOUA-I(RCB0659)