Journal
ONCOGENE
Volume 36, Issue 45, Pages 6336-6347Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2017.240
Keywords
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Funding
- Chinese Ministry of Science and Technology [2017YFA0102900]
- National Natural Science Foundation of China [81372189, 81630073]
- Science and Technology Commission of Shanghai Municipality [16JC1405700]
- KC Wong foundation
- Shanghai Eastern Hospital Stem Cell Research Base Fund
- State Key Laboratory of Oncogenes and Related Genes [90-16-03]
- Shanghai Rising-Star Program [17QA1402100]
- Shanghai Institutions of Higher Learning (The Program for Professor of Special Appointment (Young Eastern Scholar) [QD2015002]
- School of Medicine at Shanghai Jiao Tong University (Excellent Youth Scholar Initiation Grant) [16XJ11003]
- Ren Ji Hospital [RJZZ14-010]
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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.
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