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ONECUT2 is a driver of neuroendocrine prostate cancer.

Nature communications (2019-01-19)
Haiyang Guo, Xinpei Ci, Musaddeque Ahmed, Junjie Tony Hua, Fraser Soares, Dong Lin, Loredana Puca, Aram Vosoughi, Hui Xue, Estelle Li, Peiran Su, Sujun Chen, Tran Nguyen, Yi Liang, Yuzhe Zhang, Xin Xu, Jing Xu, Anjali V Sheahan, Wail Ba-Alawi, Si Zhang, Osman Mahamud, Ravi N Vellanki, Martin Gleave, Robert G Bristow, Benjamin Haibe-Kains, John T Poirier, Charles M Rudin, Ming-Sound Tsao, Bradly G Wouters, Ladan Fazli, Felix Y Feng, Leigh Ellis, Theo van der Kwast, Alejandro Berlin, Marianne Koritzinsky, Paul C Boutros, Amina Zoubeidi, Himisha Beltran, Yuzhuo Wang, Housheng Hansen He
PMID30655535
ABSTRACT

Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.