Human Prostate Cancer AGO-PAR-CLIP

MicroRNA (miRNA) deregulation in prostate cancer (PCa) contributes to PCa initiation and metastatic progression. To comprehensively define the cancer-associated changes in miRNA targeting and function in commonly studied models of PCa, we performed photoactivatable-ribonucleoside-enhanced crosslinking immunoprecipitation of the Argonaute protein (AGO-PAR-CLIP) in a panel of PCa cell lines modeling different stages of PCa progression. Using this comprehensive catalogue of miRNA targets, we analyzed miRNA targeting on known drivers of prostate cancer and examined tissue-specific and stage-specific pathway targeting by miRNAs. We found that AR is the most frequently targeted PCa oncogene and miR-148a targets the largest number of known prostate cancer drivers. Globally, tissue-specific and stage-specific changes in miRNA targeting are driven by homeostatic response to active oncogenic pathways. Our findings indicate that even in advanced PCa, the miRNA pool adapts to regulate continuing alterations in the cancer genome to balance oncogenic molecular changes. These findings are important because they are the first to globally characterize miRNA changes in prostate cancer and demonstrate how the miRNA target spectrum responds to staged tumorigenesis.