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

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


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.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Autophagy / drug effects
  • Autophagy / genetics
  • Autophagy-Related Protein 7 / genetics
  • Autophagy-Related Protein 7 / metabolism
  • Base Sequence
  • Cell Line, Tumor
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Neoplastic*
  • Genes, Reporter
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Male
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Pentacyclic Triterpenes
  • Plant Extracts / chemistry
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostate / pathology
  • RNA, Long Noncoding
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Signal Transduction
  • Tripterygium / chemistry
  • Triterpenes / pharmacology*


  • Antineoplastic Agents, Phytogenic
  • MIR17HG, human
  • MIRN20a microRNA, human
  • MicroRNAs
  • Pentacyclic Triterpenes
  • Plant Extracts
  • RNA, Long Noncoding
  • Receptors, Androgen
  • Triterpenes
  • Luciferases
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • celastrol