miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes the development of castration resistance.

Clinical intervention for patients with advanced prostate cancer (PCa) remains challenging due to the inevitable recurrence of castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT). Cancer stem cells (CSCs) with serial tumor-propagating capacity are considered to be the driving force for PCa progression and recurrence. In this study, we report that the miR-302/367 cluster, a previously identified potent pluripotency regulator, is upregulated in prostate tumors. Specifically, the forced expression of the miR-302/367 cluster accelerates the in vitro and in vivo growth of PCa cells and their resistance to androgen ablation, whereas the knockdown of the miR-302/367 cluster using anti-sense RNA suppresses the incidence of formation, growth rate and endpoint weight of PCa cell tumors. Mechanistically, we find that LATS2, a key component of the tumor-suppressive Hippo signaling pathway, acts as a direct target of the miR-302/367 cluster in PCa cells. The downregulation of LATS2 by the miR-302/367 cluster reduces the phosphorylation and enhances the nuclear translocation of the YAP oncoprotein. Conversely, the restoration of LATS2 expression abrogates the tumor-promoting effects of forced miR-302/367 cluster expression. Collectively, the potent pluripotency regulator-triggered miR-302/367/LATS2/YAP pathway is essential for prostate tumor-propagating cells and promotes castration resistance. Thus, targeting this signaling axis may represent a promising therapeutic strategy for CRPC.

Oncogene. 2017 Jul 24 [Epub]

Y Guo, J Cui, Z Ji, C Cheng, K Zhang, C Zhang, M Chu, Q Zhao, Z Yu, Y Zhang, Y-X Fang, W-Q Gao, H H Zhu

State Key Laboratory of Oncogenes and Related Genes, Ren ji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China., School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China., Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.