Abstract
Prostate cancer is an important hormone-dependent cancer affecting men. In the initial stages, prostate cancer is often treated using hormone therapy, including bicalutamide. Despite the initial effectiveness of this therapy, the tumor eventually acquires resistance, resulting in recurrence of castration-resistant prostate cancer (CRPC). Dysregulation of microRNA (miRNA) function is one of the putative underlying mechanisms of hormone therapy resistance. Reports have shown that miRNAs act as tumor suppressors in patients with prostate cancer, but the role of these molecules in bicalutamide resistance in prostate cancer cell lines remains unclear. We performed lentiviral miRNA library screening to identify novel miRNAs that modulate the response of human prostate cancer LNCaP cells to the antiandrogen bicalutamide. We found that the tumor suppressor miRNA miR-137 silenced signaling in a spectrum of human cancers and selectively targeted tripartite motif-containing 24 (TRIM24) to suppress tumor proliferation. Silencing of TRIM24 recapitulated the effect of miR-137 on cell proliferation, whereas overexpression of TRIM24 reversed this effect. Real-time reverse transcription PCR analysis revealed a reciprocal relationship between miR-137 and TRIM24 in prostate cancer cell lines and tissues. Mechanistic studies indicated that methyl CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote methylation of the miR-137 promoter and the consequent decreased transcription, leading to enhanced TRIM24 expression and glutamine metabolism. These findings describe a novel mechanism that affects TRIM24 deregulation in human cancers and provide a molecular link between miR-137, TRIM24, and tumor proliferation in CRPC.