The miR-96/RARγ signaling axis governs androgen signaling and PCa progression

RARγ (RARG) expression is commonly reduced in prostate cancer (PCa). In prostate cell models reducing RARγ expression (apo), rather than retinoid ligand (holo) had the biggest impact on prostate cell proliferation and gene expression. The apo RARγ binds at active enhancers, enriched for AR, and regulates AR signaling. Testing RARγ capacity to govern AR, by knockdown, profoundly changed dihydroxytestostone capacity to regulate cell differentiation and gene regulation. RARγ regulated genes in TCGA PCa cohorts significantly associated with more aggressive disease. RARγ downregulation was explained by a stark and common increase in miR-96 in PCa cell and animal models, and human PCa. Biochemical approaches confirmed that miR-96 directly regulates RARγ expression and function. Capture of the miR-96 targetome by biotin-miRNA pulldown identified a RARγ-centric network associated with more aggressive PCa and worse disease free survival. In summary, miR-96 targets an RARγ network to govern AR signaling and its disruption is a cancer-driver. Together, these findings support the concept that miR-96 governs the RARγ-network and prostate differentiation, in part by regulating AR. Tumors with high miR-96 and reduced RARγ-network expression significantly associated with poor disease free survival. These findings reveal how miRNA govern nuclear receptor cross-talk, and can be exploited to identify aggressive prostate cancer at an early stage.