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

Regufe da Mota, Sergio, Bailey, Sarah, Strivens, Rosemary A., Hayden, Annette L., Douglas, Leon R., Duriez, Patrick J., Borrello, M. Teresa, Benelkebir, Hanae, Ganesan, A. ORCID:, Packham, Graham and Crabb, Simon J. (2018) LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models. Cancer Cell International, 18. ISSN 1475-2867

[thumbnail of Published manuscript]
PDF (Published manuscript) - Published Version
Available under License Creative Commons Attribution.

Download (1MB) | Preview


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.

Item Type: Article
Uncontrolled Keywords: androgen receptor,lsd1,prostate cancer,castration resistance,enzalutamide,ar-v7 splice variant,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021)
Related URLs:
Depositing User: Pure Connector
Date Deposited: 25 May 2018 14:30
Last Modified: 22 Oct 2022 03:49
DOI: 10.1186/s12935-018-0568-1


Downloads per month over past year

Actions (login required)

View Item View Item