Methylation-induced silencing of miR-34a enhances chemoresistance by directly upregulating ATG4B-induced autophagy through AMPK/mTOR pathway in prostate cancer.

Abstract

miR-34a is downregulated and a regulator of drug resistance in prostate cancer (PCa). However, the mechanism of miR-34a in chemoresistance of PCa remains largely unknown. In the present study, we first confirmed the hypermethylation‑induced downregulation of miR-34a in PCa tissues and cell lines, PC-3 and DU145. Additionally, transfection of miR-34a mimics and demethylation by 5-azacytidine both resulted in the upregulation of miR-34a expression, which further induced declined cell proliferation and the enhanced apoptosis in PCa cells. Upregulation of miR-34a enhanced the chemosensitivity of PC-3 and DU145 cells. Furthermore, overexpression of miR-34a reduced the expression of autophagy-related proteins, ATG4B, Beclin-1 and LC3B II/I in PCa cells and demethylation treatment showed similar effect. ATG4B was confirmed directly by miR-34a targeting in PCa. Finally, downregulated p-AMPK and upregulated p-mTOR were detected in miR-34a overexpressed PCa cells. Collectively, miR-34a enhances chemosensitivity by directly downregulating ATG4B-induced autophagy through AMPK/mTOR pathway in PCa.