Journal
ONCOTARGET
Volume 8, Issue 8, Pages 13509-13520Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.14586
Keywords
EZH2; GSK343; miR-361; endometrial cancer; 5-AZA-CdR
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Funding
- Department of Women's Health Educational System [15K10697, 16K11123]
- Science and Technology Planning Project of Guangdong Province, China [2013B021800155]
- Grants-in-Aid for Scientific Research [15K10697, 16K11123] Funding Source: KAKEN
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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 miR361. 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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