Regulation of Docetaxel Sensitivity in Prostate Cancer Cells by Hsa-miR-125A-3P via Modulation of MTA1 Signaling

Abstract Objective To identify the potential down-stream targets of hsa-miR-125a-3p, a mature form of miR-125a, during the pathogenesis of chemoresistance in prostate cancer (PCa). Methods Expression levels of hsa-miR-125a-3p was assessed in chemoresistant PCa tissues and experimentally-established chemoresistant cells using quantitative RT-PCR (qRT-PCR). The effect of hsa-miR-125a-3p knockdown or hsa-miR-125a-3p overexpression on the Dox-induced cell death was evaluated using apoptosis ELISA in chemosensitive PC-3 cells or in chemoresistant PC-3 cells (PC-3R). Finally, using multiple assays, the regulation of Metastasis-associated protein 1 (MTA1), an essential component of the Mi-2/nucleosome remodeling deacetylation (NuRD) complex, by hsa-miR-125a-3p was studied at both molecular and functional levels. Results The expression of hsa-miR-125a-3p was significantly down-regulated in chemoresistant PCa tissues and cells. Inhibition of hsa-miR-125a-3p significantly increased docetaxel (Dox)-resistance in PC-3 cells, whereas, up-regulation of hsa-miR-125a-3p effectively reduced Dox-resistance in PC-3R, suggesting that this miRNA may act as tumor suppressor along the pathogenesis of drug resistance. Mechanistically, hsa-miR-125a-3p induced apoptosis and Dox-sensitivity in PCa cells through regulating MTA1. Conclusion Our results collectively indicate that miRNA-MTA1 can form a delicate regulatory loops to maintain a bistable state in the Dox chemosensitivity, and future endeavor in this filed should provide important clues to develop miRNA-based therapies that benefit advanced PCa patients through modulating the functional status of MTA1.