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In order to determine the expression pattern of EZH2 in ovarian neoplasms and assess the functions and mechanism of EZH2 in tumorigenesis in vitro and in vivo, we detected the protein and mRNA expression of EZH2 and p57 in normal, benign and malignant ovarian tissues, used shRNA to knock down EZH2 expression in ovarian cancer cells and established a nude mouse xenograft model. We found EZH2 was overexpressed in ovarian tumor with the highest level expression in malignant ovarian tissues, and the variation of EZH2 expression at different pathological type/grade and International Federation of Gynecology and Obstetrics (FIGO) stages was statistically significant. Furthermore, the EZH2 expression was inversely correlated with the p57 mRNA level in ovarian tissues. Moreover, inhibition of endogenous EZH2 increased the expression of p57 and reduced proliferation and migration of ovarian cancer cells. Loss of EZH2 suppresses ovarian tumor formation in vivo. Our results indicate that the EZH2 gene acts as an oncogene in tumorigenesis of ovarian cancer with the possible mechanism to suppress the anti-oncogene p57. EZH2 is a potential therapeutic target for treatment of ovarian cancer. (Cancer Sci 2011; 102: 530–539)