Aberrant overexpression of the enhancer of zeste homolog 2 (EZH2), a histone methyltransferase inhibiting targets expression via epigenetic mechanisms, is associated with an invasive phenotype and drug resistance in ovarian cancer. Breast cancer 1 (BRCA1) gene is a well-recognized tumor suppressor, whose downregulation plays a key role in the development of ovarian cancer. In the present study, we found depletion of EZH2 increased BRCA1 protein expression and promoted its nuclear translocation, but decreased BRCA1 mRNA expression. Treatment with the Akt-1 activator insulin-like growth factor-1 (IGF-1) prevented EZH2-induced BRCA1 nuclear/cytoplasmic shuttling. Loss of BRCA1 partially rescued the effects of EZH2 downregulation on proliferation, G 2/M transition, and migration in ovarian cancer cells. However, in a cisplatin-resistant sub-line of A2780 (A2780/DDP), both EZH2 and BRCA1 were overexpressed compared with parental A2780 cells and depletion of EZH2 reduced BRCA1 expression at both mRNA and protein levels. Downregulation of EZH2 or BRCA1 sensitized A2780/DDP cells to cisplatin, whereas simultaneous inhibition of them only resulted in modest resensitization instead of showing any synergistic effect because EZH2 expression was reactivated when BRCA1 expression was very low. Accordingly, our results suggest the expression of BRCA1 is modulated by EZH2 in epithelial ovarian cancer and BRCA1 is required for the effects of EZH2 downregulation on biological behaviors of tumor cells.
Keywords: BRCA1; EZH2; cell cycle; cisplatin resistance; epithelial ovarian cancer; migration; proliferation.