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Cancer Cell International
Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary Research

LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models

Authors: Sergio Regufe da Mota, Sarah Bailey, Rosemary A. Strivens, Annette L. Hayden, Leon R. Douglas, Patrick J. Duriez, M. Teresa Borrello, Hanae Benelkebir, A. Ganesan, Graham Packham, Simon J. Crabb

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7.

Methods

We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7.

Results

Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR-V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments.

Conclusion

LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Further development of this approach is warranted.
Appendix
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Metadata
Title
LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models
Authors
Sergio Regufe da Mota
Sarah Bailey
Rosemary A. Strivens
Annette L. Hayden
Leon R. Douglas
Patrick J. Duriez
M. Teresa Borrello
Hanae Benelkebir
A. Ganesan
Graham Packham
Simon J. Crabb
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0568-1

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