MicroRNA-506-3p increases the response to PARP inhibitors and cisplatin by targeting EZH2/β-catenin in serous ovarian cancers

Chemo-resistance is an important barrier to effective treatment of ovarian cancer. Poly (ADP-ribose) polymerase (PARP) inhibitors are currently promising targeted drugs used to treat BRCA-mutant ovarian cancer. Ovarian cancer patients with BRCA 1/2 mutations appear to benefit better from PARP inhibitors and chemotherapy. Understanding the mechanisms underlying PARP inhibitors and chemotherapy resistance is urgently needed. There is increasing evidence that microRNAs (miRNAs) are involved in drug resistance. MiR-506-3p is an effective inhibitor of the epithelial-to-mesenchymal transition (EMT), and can enhance chemotherapy and olaparib response in high-grade serous ovarian cancer (HGS-OvCa). Enhancer of Zeste Homolog 2 (EZH2) is considered as a direct target of miR-506-3p. The silencing of EZH2 mimics the inhibitory effects of miR-506-3p on chemo-resistance and olaparib response. Rescue of EZH2 prevented the functions of miR-506-3p. Moreover, EZH2 activates the β-catenin pathway. MiR-506-3p overexpression decreased the level of β-catenin, and the sensitivity to olaparib and cisplatin mediated by miR-506-3p was partially reversed by regulating β-catenin expression in ovarian cancer. Our results suggest that miR-506-3p increases response to PARP inhibitors and cisplatin in serous ovarian cancer by targeting EZH2/β-catenin signal pathway, which opens the possibility of using miR-506-3p overexpression as a potential therapeutic for ovarian cancer.