Methylation-induced silencing of miR-34a enhances chemoresistance by directly upregulating ATG4B-induced autophagy through AMPK/mTOR pathway in prostate cancer.
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.
Department of Urology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China.
Haiqiu
H
Liao
Department of Orthopaedics, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China.
Yang
Y
Xiao
Department of Colorectal Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.
Yingbin
Y
Hu
Department of Urology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China.
Yangming
Y
Xiao
Department of Urology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China.
Zhaofa
Z
Yin
Department of Oncology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China.
Liang
L
Liu
Department of Urology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China.
Xiaopeng
X
Kang
Department of Urology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China.
Yonggang
Y
Chen
D020413:3' Untranslated Regions; D055372:AMP-Activated Protein Kinases / Q000235:genetics; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic / Q000187:drug effects; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
D020413:3' Untranslated Regions; D000071183:Autophagy-Related Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C507524:ATG4B protein, human; D003546:Cysteine Endopeptidases; D001374:Azacitidine