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Nat Commun. 2019 Jan 17;10(1):278. doi: 10.1038/s41467-018-08133-6.

ONECUT2 is a driver of neuroendocrine prostate cancer.

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada. allen100006@gmail.com.
2
The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, V6H 3Z6, BC, Canada.
3
Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, V5Z 1L3, BC, Canada.
4
Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada.
5
Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada.
6
Weill Cornell Medicine, New York, NY, 10065, USA.
7
College of Life Sciences, Central China Normal University, Wuhan, 430079, Hubei, People's Republic of China.
8
College of Basic Medical Sciences, Dali University, Dali, 671000, Yunnan, People's Republic of China.
9
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
10
Department of Computer Science, University of Toronto, Toronto, M5T 3A1, ON, Canada.
11
Ontario Institute for Cancer Research, Toronto, M5G 0A3, ON, Canada.
12
Vector Institute, Toronto, M5G 1M1, ON, Canada.
13
Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
14
Department of Pathology, University of Toronto, Toronto, M5G 1L7, ON, Canada.
15
Department of Radiation Oncology and Institute of Medical Science, University of Toronto, Toronto, M5T 1P5, ON, Canada.
16
Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA, 94115, USA.
17
Department of Urology, University of California at San Francisco, San Francisco, CA, 94115, USA.
18
Department of Medicine, University of California at San Francisco, San Francisco, CA, 94115, USA.
19
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, 94115, USA.
20
The Broad Institute, Cambridge, MA, 02142, USA.
21
Department of Pharmacology & Toxicology, University of Toronto, Toronto, M5S 1A8, ON, Canada.
22
The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, The University of British Columbia, Vancouver, V6H 3Z6, BC, Canada. ywang@bccrc.ca.
23
Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, V5Z 1L3, BC, Canada. ywang@bccrc.ca.
24
Princess Margaret Cancer Centre, University Health Network, Toronto, M5G 1L7, ON, Canada. Hansenhe@uhnresearch.ca.
25
Department of Medical Biophysics, University of Toronto, Toronto, M5G 2M9, ON, Canada. Hansenhe@uhnresearch.ca.

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.

PMID:
30655535
PMCID:
PMC6336817
DOI:
10.1038/s41467-018-08133-6
[Indexed for MEDLINE]
Free PMC Article

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