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 Singh Chohan; Suraj Menon; Ajoeb Baridi; Wanfeng Zhao; Carlos Escriu; Clive  D'Santos; Chris Taylor; Arham Qureshi; Vincent R.  Zecchini; Greg L. Shaw; Scott M. Dehm; Ian G. Mills; James 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 Singh Chohan, Suraj Menon, Ajoeb Baridi, Wanfeng Zhao, Carlos Escriu, Clive D'Santos, Chris Taylor, Arham Qureshi, Vincent R. Zecchini, Greg L. Shaw, Scott M. Dehm, Ian G. Mills, James S. CarrollWayne D. Tilley, Iain J. McEwan, Aria Baniahmad, David E. Neal, Mohammad Asim^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 AR full-length 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 uncover novel interplay between AR and PBK that results in increased AR and ARVs expression and 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
Issue number	7
Early online date	20 Sep 2018
DOIs	https://doi.org/10.1038/s41388-018-0501-z
Publication status	Published - Sep 2019

Keywords

prostate cancer
androgen receptor
signalling kinase
transcriptional regulation
DOMAIN
ORIGINATED PROTEIN-KINASE
MITOTIC KINASE
TOPK
GENE
ANTIANDROGEN
RESISTANCE
EXPRESSION
PBK/TOPK
ABIRATERONE

UN SDGs

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

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A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer
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Final 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., D'Santos, C., Taylor, C., Qureshi, A., Zecchini, V. R., Shaw, G. L., Dehm, S. M., Mills, I. G., ... Asim, M. (2019). A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer. Oncogene, 38(7), 1136-1150. https://doi.org/10.1038/s41388-018-0501-z

Warren, AY, Massie, CE, Watt, K, Luko, K, Orafidiya, F, Selth, LA, Mohammed, H, Chohan, BS, Menon, S, Baridi, A, Zhao, W, Escriu, C, D'Santos, C, 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, no. 7, pp. 1136-1150. https://doi.org/10.1038/s41388-018-0501-z

@article{87bbf2d9786c46d680ee9166a68bec87,

title = "A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer",

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 AR full-length 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 uncover novel interplay between AR and PBK that results in increased AR and ARVs expression and executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa. ",

keywords = "prostate cancer, androgen receptor, signalling kinase, transcriptional regulation, DOMAIN, ORIGINATED PROTEIN-KINASE, MITOTIC KINASE, TOPK, GENE, ANTIANDROGEN, RESISTANCE, EXPRESSION, PBK/TOPK, ABIRATERONE",

author = "Warren, {Anne Y.} and Massie, {Charlie E.} and Kate Watt and Katarina Luko and Folake Orafidiya and Selth, {Luke A.} and Hisham Mohammed and Chohan, {Brinder Singh} and Suraj Menon and Ajoeb Baridi and Wanfeng Zhao and Carlos Escriu and Clive D'Santos and Chris Taylor and Arham Qureshi and Zecchini, {Vincent R.} and Shaw, {Greg L.} and Dehm, {Scott M.} and Mills, {Ian G.} and Carroll, {James S.} and Tilley, {Wayne D.} and McEwan, {Iain J.} and Aria Baniahmad and Neal, {David E.} and Mohammad Asim",

note = "We acknowledge support from the National Cancer Research Institute (National Institute of Health Research (NIHR) collaborative study: “Prostate Cancer: Mechanism of Progression and Treatment (PROMPT)” (grant G0500966/75466). This work was funded by a Cancer Research UK program grant (to DEN) and funding from the US Department of Defense (Prostate Cancer Research Program Transformative Impact Award, grant ID W81XWH-13- 2-0093; WDT, SMD and LAS), National Health and medical Research Council (grant ID 1083961; LAS) and PCFA/Cancer Australia/Movember (grant IDs 1012337 and 1043482; WDT and LAS). The research programs of WDT and LAS are supported by the Movember Foundation and the Prostate Cancer Foundation of Australia through the Movember Revolutionary Team Award. This work was also supported by the National Institutes of Health (NIH) grant R01CA174777 to SMD. FO was supported by a PhD project grant from Prostate Cancer UK (S10-10). LAS and MA were supported by a Young Investigator Award from the Prostate Cancer Foundation of the USA. ",

year = "2019",

month = sep,

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

language = "English",

volume = "38",

pages = "1136--1150",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "7",

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TY - JOUR

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 Singh

AU - Menon, Suraj

AU - Baridi, Ajoeb

AU - Zhao, Wanfeng

AU - Escriu, Carlos

AU - D'Santos, Clive

AU - Taylor, Chris

AU - Qureshi, Arham

AU - Zecchini, Vincent R.

AU - Shaw, Greg L.

AU - Dehm, Scott M.

AU - Mills, Ian G.

AU - Carroll, James S.

AU - Tilley, Wayne D.

AU - McEwan, Iain J.

AU - Baniahmad, Aria

AU - Neal, David E.

AU - Asim, Mohammad

N1 - We acknowledge support from the National Cancer Research Institute (National Institute of Health Research (NIHR) collaborative study: “Prostate Cancer: Mechanism of Progression and Treatment (PROMPT)” (grant G0500966/75466). This work was funded by a Cancer Research UK program grant (to DEN) and funding from the US Department of Defense (Prostate Cancer Research Program Transformative Impact Award, grant ID W81XWH-13- 2-0093; WDT, SMD and LAS), National Health and medical Research Council (grant ID 1083961; LAS) and PCFA/Cancer Australia/Movember (grant IDs 1012337 and 1043482; WDT and LAS). The research programs of WDT and LAS are supported by the Movember Foundation and the Prostate Cancer Foundation of Australia through the Movember Revolutionary Team Award. This work was also supported by the National Institutes of Health (NIH) grant R01CA174777 to SMD. FO was supported by a PhD project grant from Prostate Cancer UK (S10-10). LAS and MA were supported by a Young Investigator Award from the Prostate Cancer Foundation of the USA.

PY - 2019/9

Y1 - 2019/9

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 AR full-length 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 uncover novel interplay between AR and PBK that results in increased AR and ARVs expression and 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 AR full-length 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 uncover novel interplay between AR and PBK that results in increased AR and ARVs expression and executes AR-mediated growth and progression of PrCa, with implications for the development of PBK inhibitors for the treatment of aggressive PrCa.

KW - prostate cancer

KW - androgen receptor

KW - signalling kinase

KW - transcriptional regulation

KW - DOMAIN

KW - ORIGINATED PROTEIN-KINASE

KW - MITOTIC KINASE

KW - TOPK

KW - GENE

KW - ANTIANDROGEN

KW - RESISTANCE

KW - EXPRESSION

KW - PBK/TOPK

KW - ABIRATERONE

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UR - http://www.mendeley.com/research/reciprocal-feedback-between-pdz-binding-kinase-androgen-receptor-drives-prostate-cancer

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DO - 10.1038/s41388-018-0501-z

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C2 - 30237440

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VL - 38

SP - 1136

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JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 7

ER -

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

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Keywords

UN SDGs

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Iain McEwan

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

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Keywords

UN SDGs

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Iain McEwan

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