ONECUT2 is a driver of neuroendocrine prostate cancer

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 Kwast, Alejandro Berlin, Marianne Koritzinsky, Paul C. Boutros, Amina Zoubeidi, Himisha Beltran, Yuzhuo Wang () and Housheng Hansen He ()
Additional contact information
Haiyang Guo: University Health Network
Xinpei Ci: The University of British Columbia
Musaddeque Ahmed: University Health Network
Junjie Tony Hua: University Health Network
Fraser Soares: University Health Network
Dong Lin: The University of British Columbia
Loredana Puca: Weill Cornell Medicine
Aram Vosoughi: Weill Cornell Medicine
Hui Xue: The University of British Columbia
Estelle Li: The University of British Columbia
Peiran Su: University Health Network
Sujun Chen: University Health Network
Tran Nguyen: University Health Network
Yi Liang: University Health Network
Yuzhe Zhang: University Health Network
Xin Xu: University Health Network
Jing Xu: University Health Network
Anjali V. Sheahan: Dana-Farber Cancer Institute
Wail Ba-Alawi: University Health Network
Si Zhang: BC Cancer Research Centre
Osman Mahamud: University Health Network
Ravi N. Vellanki: University Health Network
Martin Gleave: The University of British Columbia
Robert G. Bristow: University Health Network
Benjamin Haibe-Kains: University Health Network
John T. Poirier: Memorial Sloan Kettering Cancer Center
Charles M. Rudin: Memorial Sloan Kettering Cancer Center
Ming-Sound Tsao: University Health Network
Bradly G. Wouters: University Health Network
Ladan Fazli: The University of British Columbia
Felix Y. Feng: University of California at San Francisco
Leigh Ellis: Dana-Farber Cancer Institute
Theo Kwast: University Health Network
Alejandro Berlin: University Health Network
Marianne Koritzinsky: University Health Network
Paul C. Boutros: University of Toronto
Amina Zoubeidi: The University of British Columbia
Himisha Beltran: Weill Cornell Medicine
Yuzhuo Wang: The University of British Columbia
Housheng Hansen He: University Health Network

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08133-6

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