Increased antiandrogen enzalutamide sensitivity via altering prostate cancer stem cell traits through modulating the androgen receptor-mediated CDR1/circCDR1-AS/miR-1290/BMP4 signaling.

While the recent FDA-approved antiandrogen enzalutamide (Enz) might prolong the survival of castration-resistant prostate cancer (CRPC) patients by an additional 4.8 months, most patients eventually might still develop Enz resistance within 6-12 months. Although few genes have been linked to Enz resistance in prostate cancer (PCa), the detailed mechanism(s) are still underinvestigated. Here, we found that Enz might function by altering androgen receptor(AR)-mediated CDR1/circCDR1-AS/miR-1290/BMP4 signaling to modulate PCa stem cells (CSCs) to increase Enz resistance. Mechanistic analysis revealed that Enz/AR signaling can transcriptionally regulate CDR1 expression by reducing binding to androgen response elements (AREs) on the CDR1 5' promoter to alter circCDR1-AS expression. Enz/AR/CDR1/circCDR1-AS signaling might then increase BMP4 expression by altering miR-1290 expression, which involves direct binding to the 3' UTR of BMP4 mRNA. Preclinical studies using a CWR22Rv1 xenograft mouse model and integrative analysis of GEO cohort data further demonstrated that targeting this newly identified Enz/AR/CDR1/circCDR1-AS/miR-1290/BMP4 signaling pathway with miR-1290, circCDR1-AS-shRNA, or BMP4-shRNA may help develop novel therapies to combat Enz resistance at the later stage of CRPC.