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

Kei Ihira, Peixin Dong* (Corresponding Author), Ying Xiong, Hidemichi Watari* (Corresponding Author), Yosuke Konno, Sharon J. B. Hanley, Masayuki Noguchi, Noriyuki Hirata, Futoshi Suizu, Takahiro Yamada, Masataka Kudo, Noriaki Sakuragi* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)13509-13520
Number of pages12
JournalOncotarget
Volume8
Issue number8
Early online date10 Jan 2017
DOIs
Publication statusPublished - 10 Jan 2017

Keywords

  • 5-AZA-CdR
  • endometrial cancer
  • EZH2
  • GSK343
  • miR-361

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