A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer

Anne Y. Warren; Charlie E. Massie; Kate Watt; Katarina Luko; Folake Orafidiya; Luke A. Selth; Hisham Mohammed; Brinder S. Chohan; Suraj Menon; Ajoeb Baridi; Wanfeng Zhao; Carles Escriu; Thanakorn Pungsrinont; Clive D’Santos; Xiaoping Yang; Chris Taylor; Arham Qureshi; Vincent R. Zecchini; Greg L. Shaw; Scott M. Dehm; Ian G. Mills; Jason S. Carroll; Wayne D. Tilley; Iain J. McEwan; Aria Baniahmad; David E. Neal; Mohammad Asim

doi:10.1038/s41388-018-0501-z

A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer

Anne Y. Warren, Charlie E. Massie, Kate Watt, Katarina Luko, Folake Orafidiya, Luke A. Selth, Hisham Mohammed, Brinder S. Chohan, Suraj Menon, Ajoeb Baridi, Wanfeng Zhao, Carles Escriu, Thanakorn Pungsrinont, Clive D’Santos, Xiaoping Yang, Chris Taylor, Arham Qureshi, Vincent R. Zecchini, Greg L. Shaw, Scott M. DehmIan G. Mills, Jason S. Carroll, Wayne D. Tilley, Iain J. McEwan, Aria Baniahmad, David E. Neal, Mohammad Asim

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Abstract

Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.

Original language	English
Pages (from-to)	1136-1150
Number of pages	15
Journal	Oncogene
Volume	38
Early online date	20 Sept 2018
DOIs	https://doi.org/10.1038/s41388-018-0501-z
Publication status	Published - 14 Feb 2019
Externally published	Yes

Bibliographical note

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Keywords

androgen receptor
prostate cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41388-018-0501-zLicence: CC BY

Published versionFinal published version, 3.09 MBLicence: CC BY

Cite this

Warren, A. Y., Massie, C. E., Watt, K., Luko, K., Orafidiya, F., Selth, L. A., Mohammed, H., Chohan, B. S., Menon, S., Baridi, A., Zhao, W., Escriu, C., Pungsrinont, T., D’Santos, C., Yang, X., Taylor, C., Qureshi, A., Zecchini, V. R., Shaw, G. L., ... Asim, M. (2019). A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer. Oncogene, 38, 1136-1150. https://doi.org/10.1038/s41388-018-0501-z

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abstract = "Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.",

keywords = "androgen receptor, prostate cancer",

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note = "This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.",

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doi = "10.1038/s41388-018-0501-z",

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Warren, AY, Massie, CE, Watt, K, Luko, K, Orafidiya, F, Selth, LA, Mohammed, H, Chohan, BS, Menon, S, Baridi, A, Zhao, W, Escriu, C, Pungsrinont, T, D’Santos, C, Yang, X, Taylor, C, Qureshi, A, Zecchini, VR, Shaw, GL, Dehm, SM, Mills, IG, Carroll, JS, Tilley, WD, McEwan, IJ, Baniahmad, A, Neal, DE & Asim, M 2019, 'A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer', Oncogene, vol. 38, pp. 1136-1150. https://doi.org/10.1038/s41388-018-0501-z

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T1 - A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer

AU - Warren, Anne Y.

AU - Massie, Charlie E.

AU - Watt, Kate

AU - Luko, Katarina

AU - Orafidiya, Folake

AU - Selth, Luke A.

AU - Mohammed, Hisham

AU - Chohan, Brinder S.

AU - Menon, Suraj

AU - Baridi, Ajoeb

AU - Zhao, Wanfeng

AU - Escriu, Carles

AU - Pungsrinont, Thanakorn

AU - D’Santos, Clive

AU - Yang, Xiaoping

AU - Taylor, Chris

AU - Qureshi, Arham

AU - Zecchini, Vincent R.

AU - Shaw, Greg L.

AU - Dehm, Scott M.

AU - Mills, Ian G.

AU - Carroll, Jason S.

AU - Tilley, Wayne D.

AU - McEwan, Iain J.

AU - Baniahmad, Aria

AU - Neal, David E.

AU - Asim, Mohammad

N1 - This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PY - 2019/2/14

Y1 - 2019/2/14

N2 - Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.

AB - Elucidation of mechanisms underlying the increased androgen receptor (AR) activity and subsequent development of aggressive prostate cancer (PrCa) is pivotal in developing new therapies. Using a systems biology approach, we interrogated the AR-regulated proteome and identified PDZ binding kinase (PBK) as a novel AR-regulated protein that regulates full-length AR and AR variants (ARVs) activity in PrCa. PBK overexpression in aggressive PrCa is associated with early biochemical relapse and poor clinical outcome. In addition to its carboxy terminus ligand-binding domain, PBK directly interacts with the amino terminus transactivation domain of the AR to stabilise it thereby leading to increased AR protein expression observed in PrCa. Transcriptome sequencing revealed that PBK is a mediator of global AR signalling with key roles in regulating tumour invasion and metastasis. PBK inhibition decreased growth of PrCa cell lines and clinical specimen cultured ex vivo. We uncovered a novel interplay between AR and PBK that results in increased AR and ARVs expression that executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.

KW - androgen receptor

KW - prostate cancer

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ER -

A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer

Abstract

Bibliographical note

Keywords

UN SDGs

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