title: Downregulation of miR-17-92a cluster promotes autophagy induction in response to celastrol treatment in prostate cancer cells.
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.
authors: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors: Jianquan
authors: J
authors: Guo
authors: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors: Yu
authors: Y
authors: Mei
authors: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors: Kai
authors: K
authors: Li
authors: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
authors: Xuemei
authors: X
authors: Huang
authors: School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China. Electronic address: yanghj@hit.edu.cn.
authors: Huanjie
authors: H
authors: Yang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071193:Autophagy-Related Protein 7 / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts / Q000737:chemistry; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D029757:Tripterygium / Q000737:chemistry; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C568997:MIR17HG, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D053978:Pentacyclic Triterpenes; D010936:Plant Extracts; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen; D014315:Triterpenes; D008156:Luciferases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; C050414:celastrol
keywords: Androgen receptor; Autophagy; Celastrol; Prostate cancer; miR-17-92a