Fan Aoyu, Zhang Yunyan, Li Yunpeng, Meng Wei, Wu Fan, Pan Wei, Ma Zhongliang, Chen Wei
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200030, China.
Lab for Noncoding RNA and Cancer, School of Life Sciences, Shanghai University, Shanghai, 200444, China.
Adv Sci (Weinh). 2025 Feb;12(8):e2411675. doi: 10.1002/advs.202411675. Epub 2025 Jan 9.
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.
前列腺癌（PCa）是全球男性中最常见的恶性肿瘤之一。雄激素剥夺疗法（ADT）最初在治疗PCa方面显示出显著疗效；然而，大多数PCa病例最终会进展为去势抵抗性前列腺癌（CRPC），其治疗变得越来越具有挑战性。值得注意的是，PCa细胞中初级纤毛的缺失或破坏可能在疾病进展中起关键作用，并且关于环状RNA在纤毛发生中的作用尚无报道。因此，这值得进一步研究。在本研究中，鉴定了与前列腺癌进展和恩杂鲁胺耐药相关的关键环状RNA。具体而言，发现hsa_circ_0005185与OTUB1和RAB8A相互作用，充当分子支架。Hsa_circ_0005185介导去泛素化酶OTUB1与RAB8A的结合，导致RAB8A去泛素化。因此，RAB8A的稳定表达促进初级纤毛的再生，并增强Hedgehog信号通路中的抑制因子GLI3R的产生，从而抑制AR活性并减缓CRPC的进展。
