Regulation of Docetaxel Sensitivity in Prostate Cancer Cells by hsa-miR-125a-3p via Modulation of Metastasis-Associated Protein 1 Signaling

OBJECTIVE To identify the potential downstream targets of hsa-miR-125a-3p, a mature form of miR-125a, during the pathogenesis of chemoresistance in prostate cancer (PCa). MATERIALS AND METHODS The expression levels of hsa-miR-125a-3p were assessed in chemoresistant PCa tissues and experimentally established chemoresistant cells using quantitative reverse transcription-polymerase chain reaction. 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 complex, by hsa-miR-125a-3p was studied at both molecular and functional levels. RESULTS The expression of hsa-miR-125a-3p was significantly downregulated in chemoresistant PCa tissues and cells. Inhibition of hsa-miR-125a-3p significantly increased docetaxel (Dox) resistance in PC-3 cells, whereas upregulation of hsa-miR-125a-3p effectively reduced Dox resistance in PC-3R, suggesting that this microRNA (miRNA) may act as a 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 loop 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. (C) 2017 Published by Elsevier Inc.