The miR-96 and RARγ signaling axis governs androgen signaling and prostate cancer progression

Oncogene. 2019 Jan;38(3):421-444. doi: 10.1038/s41388-018-0450-6. Epub 2018 Aug 17.

Abstract

Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARγ) are commonly reduced in prostate cancer (PCa). Therefore, we sought to establish the cellular and gene regulatory consequences of reduced RARγ expression, and determine RARγ regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARγ levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARγ cistrome, which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARγ to regulate androgen signaling, RARγ knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARγ downregulation was explained by increased miR-96 in PCa cell and mouse models, and TCGA PCa cohorts. Biochemical approaches confirmed that miR-96 directly regulated RARγ expression and function. Capture of the miR-96 targetome by biotin-miR-96 identified that RARγ and a number of RARγ interacting co-factors including TACC1 were all targeted by miR-96, and expression of these genes were prominently altered, positively and negatively, in the TCGA-PRAD cohort. Differential gene expression analyses between tumors in the TCGA-PRAD cohort with lower quartile expression levels of RARG and TACC1 and upper quartile miR-96, compared to the reverse, identified a gene network including several RARγ target genes (e.g., SOX15) that significantly associated with worse disease-free survival (hazard ratio 2.23, 95% CI 1.58 to 2.88, p = 0.015). In summary, miR-96 targets a RARγ network to govern AR signaling, PCa progression and disease outcome.

Publication types

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

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology*
  • Androgens*
  • Animals
  • Cell Line, Tumor
  • Disease Progression
  • Enhancer Elements, Genetic
  • Fetal Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • MicroRNAs / physiology*
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Neoplasms, Hormone-Dependent / genetics
  • Neoplasms, Hormone-Dependent / metabolism
  • Neoplasms, Hormone-Dependent / mortality
  • Neoplasms, Hormone-Dependent / pathology*
  • Nuclear Proteins / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / pathology*
  • RNA Interference
  • RNA, Neoplasm / physiology*
  • RNA, Small Interfering / genetics
  • Receptors, Androgen / metabolism
  • Receptors, Retinoic Acid / physiology*
  • Retinoic Acid Receptor gamma
  • Signal Transduction

Substances

  • Androgens
  • Fetal Proteins
  • MIRN96 microRNA, human
  • MicroRNAs
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • RNA, Neoplasm
  • RNA, Small Interfering
  • Receptors, Androgen
  • Receptors, Retinoic Acid
  • TACC1 protein, human