Circadian rhythm-related miR-6883-5p suppresses enzalutamide-resistant prostate cancer

The increasing incidence of prostate cancer (PCa), particularly the emergence of treatment-resistant castration-resistant prostate cancer (CRPC), has intensified research efforts to address this lethal disease. Circadian rhythm gene alterations have been identified as critical factors influencing PCa progression and treatment resistance, warranting further investigation into their roles in PCa biology. In this study, we identified a significant downregulation of <i>PER1</i> and its associated miRNA, miR-6883-5p, in PCa cells and clinical samples, suggesting their potential clinical relevance. Functional analyses demonstrated that miR-6883-5p suppresses the proliferation of enzalutamide-resistant PCa cells both in vitro and in vivo by directly targeting AR-V7. Furthermore, we delineated the regulatory functions of the transcription factors BMAL1 and CLOCK in promoting the expression of <i>PER1</i> and miR-6883-5p, while miR-6883-5p negatively regulates CLOCK expression, thereby impacting the transcription-translation feedback loop (TTFL) of circadian genes. Collectively, these findings uncover a regulatory axis involving circadian rhythm components, miR-6883-5p, AR-V7, and PCa progression, providing new mechanistic insights into treatment resistance in CRPC and highlighting the circadian clock as a potential therapeutic target.