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

Yan Zhang1,2, Dayong Zheng1,3, Ting Zhou1,4

  • 1Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.

Nature Communications
|October 6, 2018
PubMed

Insights

Rising aggressive neuroendocrine prostate cancer (NEPC) is linked to androgen-deprivation therapy (ADT). A new CREB/EZH2/TSP1 pathway drives NEPC progression by promoting neuroendocrine differentiation and angiogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Androgen-deprivation therapy (ADT) for prostate cancer can lead to aggressive neuroendocrine prostate cancer (NEPC).
  • The mechanisms driving neuroendocrine differentiation (NED) and angiogenesis in NEPC remain poorly understood.
  • EZH2 (enhancer of zeste homolog 2) has emerged as a key regulator in cancer progression.

Purpose of the Study:

  • To elucidate the molecular mechanisms connecting NED and angiogenesis in NEPC.
  • To identify key regulators and pathways involved in ADT-induced NEPC.
  • To investigate the role of EZH2, CREB, and TSP1 in NEPC development.

Main Methods:

  • Investigated the role of EZH2 in regulating NED and angiogenesis.
  • Examined the impact of ADT-activated CREB (cAMP response element-binding protein) on EZH2 activity.
  • Analyzed TSP1 (thrombospondin-1, THBS1) as a direct target of EZH2.
  • Utilized prostate cancer patient samples and in vivo tumor xenograft models.

Main Results:

  • ADT-activated CREB enhances EZH2 activity, promoting both NED and angiogenesis.
  • EZH2 epigenetically represses the anti-angiogenic factor TSP1, leading to its downregulation.
  • Castration activates the CREB/EZH2 axis, impacting TSP1, angiogenesis, and NE phenotypes in xenografts.
  • Inhibition of CREB suppressed the CREB/EZH2 axis, tumor growth, NED, and angiogenesis in vivo.

Conclusions:

  • A novel CREB/EZH2/TSP1 pathway is identified as critical in ADT-enhanced NED and angiogenesis.
  • This pathway contributes to prostate cancer progression towards NEPC.
  • Targeting this pathway may offer new therapeutic strategies for NEPC.

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