EZH2 Exacerbates Breast Cancer by Methylating and Activating STAT3 Directly

Breast cancer is one of the most common causes of female death globally. Numerous clinical drugs for breast cancer have been developed, but the unsatisfactory, inevitable side effects and drug resistance are the emerging threatens. Therefore, it is necessary to investigate the comprehensive mechanism of breast cancer. Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver in diverse cancers, such as breast cancer. The canonical role of EZH2 has been vastly investigated, but the non-canonical function of EZH2 in breast cancer remains unclear. Here, we demonstrated that EZH2 exacerbated breast cancer in non-canonical manner by methylating STAT3. EZH2 over-expressed in breast cancer patients and regulated STAT3 post-transcriptionally according to TCGA datasets. Chemical and genetic inhibition of EZH2 impeded proliferation and migration of breast cancer cells, which may be partially rescued by STAT3 over-expression. EZH2 physically interacted with STAT3 and methylated STAT3 directly, resulting in increased nuclear localization and chromatin of STAT3. Furthermore, the mutation of STAT3 methylation site, targeted by EZH2, impeded the transcriptional activity of STAT3. Eventually, disturbed STAT3 methylation by EZH2 in animal model showed decreased breast cancer growth. These data confirm that EZH2 exacerbates breast cancer by methylating STAT3 directly, and thus providing a promising therapeutic target for breast cancer.