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ONECUT2 is a driver of neuroendocrine prostate cancer

Author

Listed:
  • Haiyang Guo

    (University Health Network)

  • Xinpei Ci

    (The University of British Columbia
    BC Cancer Research Centre)

  • Musaddeque Ahmed

    (University Health Network)

  • Junjie Tony Hua

    (University Health Network
    University of Toronto)

  • Fraser Soares

    (University Health Network)

  • Dong Lin

    (The University of British Columbia
    BC Cancer Research Centre)

  • Loredana Puca

    (Weill Cornell Medicine)

  • Aram Vosoughi

    (Weill Cornell Medicine)

  • Hui Xue

    (The University of British Columbia
    BC Cancer Research Centre)

  • Estelle Li

    (The University of British Columbia)

  • Peiran Su

    (University Health Network
    University of Toronto)

  • Sujun Chen

    (University Health Network
    University of Toronto)

  • Tran Nguyen

    (University Health Network)

  • Yi Liang

    (University Health Network)

  • Yuzhe Zhang

    (University Health Network
    Central China Normal University
    Dali University)

  • Xin Xu

    (University Health Network)

  • Jing Xu

    (University Health Network)

  • Anjali V. Sheahan

    (Dana-Farber Cancer Institute)

  • Wail Ba-Alawi

    (University Health Network
    University of Toronto)

  • Si Zhang

    (BC Cancer Research Centre)

  • Osman Mahamud

    (University Health Network
    University of Toronto)

  • Ravi N. Vellanki

    (University Health Network)

  • Martin Gleave

    (The University of British Columbia)

  • Robert G. Bristow

    (University Health Network
    University of Toronto)

  • Benjamin Haibe-Kains

    (University Health Network
    University of Toronto
    University of Toronto
    Ontario Institute for Cancer Research)

  • John T. Poirier

    (Memorial Sloan Kettering Cancer Center)

  • Charles M. Rudin

    (Memorial Sloan Kettering Cancer Center)

  • Ming-Sound Tsao

    (University Health Network
    University of Toronto)

  • Bradly G. Wouters

    (University Health Network
    University of Toronto
    University of Toronto)

  • Ladan Fazli

    (The University of British Columbia)

  • Felix Y. Feng

    (University of California at San Francisco
    University of California at San Francisco
    University of California at San Francisco
    Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco)

  • Leigh Ellis

    (Dana-Farber Cancer Institute
    The Broad Institute)

  • Theo Kwast

    (University Health Network
    University of Toronto)

  • Alejandro Berlin

    (University Health Network
    University of Toronto)

  • Marianne Koritzinsky

    (University Health Network
    University of Toronto)

  • Paul C. Boutros

    (University of Toronto
    Ontario Institute for Cancer Research
    University of Toronto)

  • Amina Zoubeidi

    (The University of British Columbia)

  • Himisha Beltran

    (Weill Cornell Medicine)

  • Yuzhuo Wang

    (The University of British Columbia
    BC Cancer Research Centre)

  • Housheng Hansen He

    (University Health Network
    University of Toronto)

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.

Suggested Citation

  • 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, 2019. "ONECUT2 is a driver of neuroendocrine prostate cancer," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08133-6
    DOI: 10.1038/s41467-018-08133-6
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    Cited by:

    1. Avradip Chatterjee & Brad Gallent & Madhusudhanarao Katiki & Chen Qian & Matthew R. Harter & Steve Silletti & Elizabeth A. Komives & Michael R. Freeman & Ramachandran Murali, 2024. "The homeodomain regulates stable DNA binding of prostate cancer target ONECUT2," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Goutam Chakraborty & Kasmira Gupta & Natasha Kyprianou, 2023. "Epigenetic mechanisms underlying subtype heterogeneity and tumor recurrence in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    3. Zhao Wei & Song Wang & Yaning Xu & Wenzheng Wang & Fraser Soares & Musaddeque Ahmed & Ping Su & Tingting Wang & Elias Orouji & Xin Xu & Yong Zeng & Sujun Chen & Xiaoyu Liu & Tianwei Jia & Zhaojian Liu, 2023. "MYC reshapes CTCF-mediated chromatin architecture in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Zifeng Wang & Scott L. Townley & Songqi Zhang & Mingyu Liu & Muqing Li & Maryam Labaf & Susan Patalano & Kavita Venkataramani & Kellee R. Siegfried & Jill A. Macoska & Dong Han & Shuai Gao & Gail P. R, 2024. "FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Meixia Che & Aashi Chaturvedi & Sarah A. Munro & Samuel P. Pitzen & Alex Ling & Weijie Zhang & Josh Mentzer & Sheng-Yu Ku & Loredana Puca & Yanyun Zhu & Andries M. Bergman & Tesa M. Severson & Colleen, 2021. "Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    6. Yue Deng & Yuqi Lin & Siyu Chen & Yuhang Xiang & Hongjia Chen & Shuyuan Qi & Hyung Suk Oh & Biswajit Das & Gloria Komazin-Meredith & Jean M. Pesola & David M. Knipe & Donald M. Coen & Dongli Pan, 2024. "Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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