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

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

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.

Journal Article
1475-2867
1-9
Regufe da Mota, Sergio
fe39404b-e413-4834-97c6-0f2204b500a9
Bailey, Sarah
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Strivens, Rosemary A.
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Hayden, Annette L.
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Douglas, Leon R.
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Duriez, Patrick J.
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Borrello, M. Teresa
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Benelkebir, Hanae
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Ganesan, A.
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Packham, Graham
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Crabb, Simon J.
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Regufe da Mota, Sergio
fe39404b-e413-4834-97c6-0f2204b500a9
Bailey, Sarah
f9e7aa1b-4b6f-47c8-a8cb-afb40d6d5f5e
Strivens, Rosemary A.
563a181f-b650-418d-9f33-acde81e10908
Hayden, Annette L.
3a43aee1-3ff0-4182-956d-b6c7b3a7f8be
Douglas, Leon R.
049b5f33-6870-4773-ae34-663489b472ba
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Borrello, M. Teresa
dd1342c1-f2e3-4b2e-a51e-50fc74797c1f
Benelkebir, Hanae
fbfb761f-8f66-4729-b376-6a228b28f142
Ganesan, A.
1368ebfa-9998-4ffc-a0da-6ca25d29e6b8
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373

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., 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 (71), 1-9. (doi:10.1186/s12935-018-0568-1).

Record type: Article

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.

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More information

Accepted/In Press date: 30 April 2018
e-pub ahead of print date: 9 May 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 421010
URI: https://eprints.soton.ac.uk/id/eprint/421010
ISSN: 1475-2867
PURE UUID: 283e0a84-2d0f-44a5-8fea-b5b76be67932
ORCID for Sergio Regufe da Mota: ORCID iD orcid.org/0000-0002-8127-5246
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 21 May 2018 16:30
Last modified: 14 Mar 2019 01:47

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Contributors

Author: Sarah Bailey
Author: Rosemary A. Strivens
Author: Annette L. Hayden
Author: Leon R. Douglas
Author: Patrick J. Duriez
Author: M. Teresa Borrello
Author: Hanae Benelkebir
Author: A. Ganesan
Author: Graham Packham ORCID iD
Author: Simon J. Crabb

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