Ubiquitin-conjugating enzyme E2C () plays important roles in tumor progression; nevertheless, its function in endometrial cancer remains unclear. This study elucidated the impact of on endometrial cancer and its underlying mechanism. Human endometrial cancer and normal endometrial tissues were acquired from patients at Wuhan Union Hospital and expression was detected by Western blotting and qRT-PCR. Endometrial cancer cells were transfected with a overexpression plasmid or -specific short hairpin RNA (shRNA) to up- or downregulate expression, respectively. CCK8 and transwell assays were applied to assess the effects of on cell proliferation, migration, and invasion. We found a significant elevation of expression in patients with endometrial cancer, and that upregulation was associated with advanced histologic grade, FIGO stage, recurrence, and shorter overall survival. knockdown inhibited endometrial cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas overexpression exerted the opposite effects. downregulation increased p53 and its downstream p21 expression, with p53 overexpression reversing the EMT-promoting effects of . enhanced p53 ubiquitination to facilitate its degradation in endometrial cancer cells. Estradiol (E2) induced expression via estrogen receptor α, which binds directly to the promoter element. Silencing of inhibited E2-promoted migration, invasion, and EMT and . IMPLICATIONS: -mediated tumor EMT promotion by estrogen is a novel mechanism for the progression of estrogen-induced endometrial cancer, which could offer new biomarkers for diagnosis and therapy of endometrial cancer in the future.