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

Liao,Haiqiu; Xiao,Yang; Hu,Yingbin; Xiao,Yangming; Yin,Zhaofa; Liu,Liang; Kang,Xiaopeng; Chen,Yonggang

doi:10.3892/or.2015.4331

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

Authors:
- Haiqiu Liao
- Yang Xiao
- Yingbin Hu
- Yangming Xiao
- Zhaofa Yin
- Liang Liu
- Xiaopeng Kang
- Yonggang Chen
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Affiliations: Department of Urology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China, Department of Orthopaedics, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China, Department of Colorectal Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China, Department of Oncology, Loudi Central Hospital of Hunan Province, Loudi, Hunan 417000, P.R. China
Published online on: October 16, 2015 https://doi.org/10.3892/or.2015.4331
Pages: 64-72

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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.

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