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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer

Sergio Regufe da Mota1, Sarah Bailey1, Rosemary A Strivens1

  • 1Cancer Sciences Unit and Cancer Research UK Centre, University of Southampton, Southampton General Hospital, Somers Cancer Research Building, Mailpoint 824, Southampton, SO16 6YD UK.

Cancer Cell International
|May 16, 2018
PubMed
Abstract

Insights

Lysine demethylase LSD1 inhibition reduces androgen receptor activation in castrate resistant prostate cancer (CRPC) models. This indicates LSD1 is a potential therapeutic target for CRPC driven by androgen receptor variants like AR-V7.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Castrate resistant prostate cancer (CRPC) often involves androgen receptor (AR) variants like AR-V7, leading to resistance against therapies such as enzalutamide.
  • Lysine demethylase LSD1 functions as a co-activator for wild-type AR and is a therapeutic target in hormone-sensitive prostate cancer.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting LSD1 in CRPC models, specifically those driven by the AR-V7 splice variant.

Main Methods:

  • Utilized cell line models of CRPC engineered to overexpress AR-V7.
  • Assessed the impact of chemical LSD1 inhibition on AR activation.
  • Validated findings using LSD1 depletion experiments and prostate cancer cell lines expressing AR-V7.

Main Results:

  • Chemical inhibition of LSD1 significantly reduced AR activation for both wild-type AR and the AR-V7 splice variant.
  • Findings were confirmed through luciferase reporter assays and in LNCaP and 22Rv1 prostate cancer cell lines.

Conclusions:

  • LSD1 plays a crucial role in activating both wild-type and AR-V7 splice variant forms of the androgen receptor.
  • LSD1 represents a viable therapeutic target for CRPC models, warranting further investigation and development.
Keywords:
AR-V7 splice variantAndrogen receptorCastration resistanceEnzalutamideLSD1Prostate cancer

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