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Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers

Author

Listed:
  • Yan Zhang

    (University of Texas Health Science Center at Houston
    Huazhong University of Science and Technology)

  • Dayong Zheng

    (University of Texas Health Science Center at Houston
    Southern Medical University)

  • Ting Zhou

    (University of Texas Health Science Center at Houston
    Southern Medical University)

  • Haiping Song

    (University of Texas Health Science Center at Houston
    Huazhong University of Science and Technology)

  • Mohit Hulsurkar

    (University of Texas Health Science Center at Houston
    University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences)

  • Ning Su

    (University of Texas Health Science Center at Houston
    Guangzhou Chest Hospital)

  • Ying Liu

    (University of Texas Health Science Center at Houston
    Central South University)

  • Zheng Wang

    (University of Texas Health Science Center at Houston)

  • Long Shao

    (Baylor College of Medicine, and Michael E. DeBakey VAMC)

  • Michael Ittmann

    (Baylor College of Medicine, and Michael E. DeBakey VAMC)

  • Martin Gleave

    (University of British Columbia)

  • Huanxing Han

    (Changzheng Hospital)

  • Feng Xu

    (Southern Medical University)

  • Wangjun Liao

    (Southern Medical University)

  • Hongbo Wang

    (Huazhong University of Science and Technology)

  • Wenliang Li

    (University of Texas Health Science Center at Houston
    University of Texas Health Science Center at Houston
    University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences)

Abstract

The incidence of aggressive neuroendocrine prostate cancers (NEPC) related to androgen-deprivation therapy (ADT) is rising. NEPC is still poorly understood, such as its neuroendocrine differentiation (NED) and angiogenic phenotypes. Here we reveal that NED and angiogenesis are molecularly connected through EZH2 (enhancer of zeste homolog 2). NED and angiogenesis are both regulated by ADT-activated CREB (cAMP response element-binding protein) that in turn enhances EZH2 activity. We also uncover anti-angiogenic factor TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2 epigenetic repression. TSP1 is downregulated in advanced prostate cancer patient samples and negatively correlates with NE markers and EZH2. Furthermore, castration activates the CREB/EZH2 axis, concordantly affecting TSP1, angiogenesis and NE phenotypes in tumor xenografts. Notably, repressing CREB inhibits the CREB/EZH2 axis, tumor growth, NED, and angiogenesis in vivo. Taken together, we elucidate a new critical pathway, consisting of CREB/EZH2/TSP1, underlying ADT-enhanced NED and angiogenesis during prostate cancer progression.

Suggested Citation

  • Yan Zhang & Dayong Zheng & Ting Zhou & Haiping Song & Mohit Hulsurkar & Ning Su & Ying Liu & Zheng Wang & Long Shao & Michael Ittmann & Martin Gleave & Huanxing Han & Feng Xu & Wangjun Liao & Hongbo W, 2018. "Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06177-2
    DOI: 10.1038/s41467-018-06177-2
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