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.