ONECUT2 is a driver of neuroendocrine prostate cancer Journal Article


Authors: Guo, H.; Ci, X.; Ahmed, M.; Hua, J. T.; Soares, F.; Lin, D.; Puca, L.; Vosoughi, A.; Xue, H.; Li, E.; Su, P.; Chen, S.; Nguyen, T.; Liang, Y.; Zhang, Y.; Xu, X.; Xu, J.; Sheahan, A. V.; Ba-Alawi, W.; Zhang, S.; Mahamud, O.; Vellanki, R. N.; Gleave, M.; Bristow, R. G.; Haibe-Kains, B.; Poirier, J. T.; Rudin, C. M.; Tsao, M. S.; Wouters, B. G.; Fazli, L.; Feng, F. Y.; Ellis, L.; van der Kwast, T.; Berlin, A.; Koritzinsky, M.; Boutros, P. C.; Zoubeidi, A.; Beltran, H.; Wang, Y.; He, H. H.
Article Title: ONECUT2 is a driver of neuroendocrine prostate cancer
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. © 2019, The Author(s).
Journal Title: Nature Communications
Volume: 10
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2019-01-17
Start Page: 278
Language: English
DOI: 10.1038/s41467-018-08133-6
PUBMED: 30655535
PROVIDER: scopus
PMCID: PMC6336817
DOI/URL:
Notes: Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Charles Rudin
    154 Rudin
  2. John Thomas Poirier
    53 Poirier