| First Author | Long MD | Year | 2019 |
| Journal | Oncogene | Volume | 38 |
| Issue | 3 | Pages | 421-444 |
| PubMed ID | 30120411 | Mgi Jnum | J:269944 |
| Mgi Id | MGI:6273574 | Doi | 10.1038/s41388-018-0450-6 |
| Citation | Long MD, et al. (2018) The miR-96 and RARgamma signaling axis governs androgen signaling and prostate cancer progression. Oncogene |
| abstractText | Expression levels of retinoic acid receptor gamma (NR1B3/RARG, encodes RARgamma) are commonly reduced in prostate cancer (PCa). Therefore, we sought to establish the cellular and gene regulatory consequences of reduced RARgamma expression, and determine RARgamma regulatory mechanisms. RARG shRNA approaches in non-malignant (RWPE-1 and HPr1-AR) and malignant (LNCaP) prostate models revealed that reducing RARgamma levels, rather than adding exogenous retinoid ligand, had the greatest impact on prostate cell viability and gene expression. ChIP-Seq defined the RARgamma cistrome, which was significantly enriched at active enhancers associated with AR binding sites. Reflecting a significant genomic role for RARgamma to regulate androgen signaling, RARgamma knockdown in HPr1-AR cells significantly regulated the magnitude of the AR transcriptome. RARgamma 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 RARgamma expression and function. Capture of the miR-96 targetome by biotin-miR-96 identified that RARgamma and a number of RARgamma 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 RARgamma 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 RARgamma network to govern AR signaling, PCa progression and disease outcome. |
