Primary Cilia Formation Mediated by Hsa_Circ_0005185/OTUB1/RAB8A Complex Inhibits Prostate Cancer Progression by Suppressing Hedgehog Signaling Pathway

Abstract Prostate cancer (PCa) is one of the most common malignancies for male individuals globally. Androgen deprivation therapy (ADT) initially demonstrated significant efficacy in treating PCa; however, most cases of PCa eventually progress to castration‐resistant prostate cancer (CRPC), which becomes increasingly challenging to manage. Notably, the loss or disruption of primary cilia in PCa cells may play a critical role in the progression of the disease, and there are no reports on the role of circular RNAs in ciliogenesis. Thus, this warrants further investigation.In this study, key circular RNAs linked to prostate cancer progression, and enzalutamide resistance is identified. Specifically, it is found that hsa_circ_0005185 interacts with OTUB1 and RAB8A, serving as a molecular scaffold. Hsa_circ_0005185 mediates the binding of the deubiquitinase OTUB1 to RAB8A, resulting in the deubiquitination of RAB8A. Consequently, the stable expression of RAB8A promotes the regeneration of primary cilia and enhances the production of GLI3R, an inhibitory factor in the Hedgehog signaling pathway, thereby suppressing AR activity and slowing the progression of CRPC.