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Biochem Biophys Res Commun. 2016 Sep 16;478(2):804-10. doi: 10.1016/j.bbrc.2016.08.029. Epub 2016 Aug 5.

Downregulation of miR-17-92a cluster promotes autophagy induction in response to celastrol treatment in prostate cancer cells.

Author information

1
School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
2
School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China. Electronic address: yanghj@hit.edu.cn.

Abstract

Celastrol has potential application for the treatment of prostate cancer. However it causes autophagy as a protective response in prostate and other types of cancers, thus unveiling the underlying mechanisms may benefit its future application. In the present study, we demonstrate that the miR-17-92a cluster plays a negative role in celastrol induced-autophagy. Dissection of miR-17-92a cluster revealed the role of miR-17 seed family (miR-20a and miR-17) in autophagy inhibition in the context of prostate cancer cells. Autophagy-related gene ATG7 was validated as a target of miR-17 seed family by dual-luciferase assay and qPCR. Celastrol induced autophagy was inhibited by miR-20a or miR-17, while the inhibitory effects were rescued in the presence of pcDNA-ATG7 lacking 3' UTR, demonstrating that these two members target ATG7 to inhibit celastrol-induced autophagy. As celastrol degrades androgen receptor (AR), a key transcription factor in prostate cancer cells, we further investigated whether AR affected miR-17-92a expression in prostate cancer cells. AR binding sites were found in the promoter and two introns of miR-17-92a. In addition, higher expression levels of miR-17-92a were observed in AR positive cells compared with AR negative cells. Ectopic expression of AR could enhance the expression of miR-17-92a cluster in AR-negative prostate cancer cells while knockdown of AR decreased miR-17-92a expression in AR-positive cells, demonstrating the regulation of AR on miR-17-92a transcription. In summary, our results demonstrate that celastrol downregulates AR and its target miR-17-92a, leading to autophagy induction in prostate cancer cells.

KEYWORDS:

Androgen receptor; Autophagy; Celastrol; Prostate cancer; miR-17-92a

PMID:
27501757
DOI:
10.1016/j.bbrc.2016.08.029
[Indexed for MEDLINE]

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