miR-22 and miR-29a Are Members of the Androgen Receptor Cistrome Modulating LAMC1 and Mcl-1 in Prostate Cancer

Mol Endocrinol. 2015 Jul;29(7):1037-54. doi: 10.1210/me.2014-1358. Epub 2015 Jun 8.

Abstract

The normal prostate as well as early stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR disclosed the existence of an intricate network between AR, miRNAs and downstream target genes. In this study DUCaP cells, characterized by high content of wild-type AR and robust AR transcriptional activity, were chosen as the main experimental model. By integrative analysis of chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray expression profiling data, miRNAs putatively bound and significantly regulated by AR were identified. A direct AR regulation of miR-22, miR-29a, and miR-17-92 cluster along with their host genes was confirmed. Interestingly, endogenous levels of miR-22 and miR-29a were found to be reduced in PCa cells expressing AR. In primary tumor samples, miR-22 and miR-29a were less abundant in the cancerous tissue compared with the benign counterpart. This specific expression pattern was associated with a differential DNA methylation of the genomic AR binding sites. The identification of laminin gamma 1 (LAMC1) and myeloid cell leukemia 1 (MCL1) as direct targets of miR-22 and miR-29a, respectively, suggested a tumor-suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in PCa cells induced apoptosis and diminished cell migration and viability. Collectively, these data provide additional information regarding the complex regulatory machinery that guides miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genome*
  • Humans
  • Laminin / genetics*
  • Laminin / metabolism
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • AR protein, human
  • Androgens
  • Laminin
  • MCL1 protein, human
  • MIRN22 microRNA, human
  • MIRN29 microRNA, human
  • MicroRNAs
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Receptors, Androgen
  • laminin gamma 1