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 & 5 others Wayne D. Tilley, Iain J. McEwan, Aria Baniahmad, David E. Neal, Mohammad Asim*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)
5 Downloads (Pure)

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 languageEnglish
Pages (from-to)1136-1150
Number of pages15
JournalOncogene
Volume38
Issue number7
Early online date20 Sep 2018
DOIs
Publication statusPublished - 2019

Fingerprint

Androgen Receptors
Prostatic Neoplasms
PDZ-binding kinase
Systems Biology
Proteome
Growth
Transcriptome
Transcriptional Activation
Proteins
Neoplasm Metastasis
Ligands
Recurrence
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Cancer Research

Cite this

Warren, A. Y., Massie, C. E., Watt, K., Luko, K., Orafidiya, F., Selth, L. A., ... 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

A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer. / Warren, Anne Y.; Massie, Charlie E.; Watt, Kate; Luko, Katarina; Orafidiya, Folake; Selth, Luke A.; Mohammed, Hisham; Chohan, Brinder Singh; Menon, Suraj; Baridi, Ajoeb; Zhao, Wanfeng; Escriu, Carlos; D'Santos, Clive ; Taylor, Chris; Qureshi, Arham; Zecchini, Vincent R. ; Shaw, Greg L.; Dehm, Scott M.; Mills, Ian G.; Carroll, James S.; Tilley, Wayne D.; McEwan, Iain J.; Baniahmad, Aria; Neal, David E.; Asim, Mohammad (Corresponding Author).

In: Oncogene, Vol. 38, No. 7, 2019, p. 1136-1150.

Research output: Contribution to journalArticle

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
Warren, Anne Y. ; Massie, Charlie E. ; Watt, Kate ; Luko, Katarina ; Orafidiya, Folake ; Selth, Luke A. ; Mohammed, Hisham ; Chohan, Brinder Singh ; Menon, Suraj ; Baridi, Ajoeb ; Zhao, Wanfeng ; Escriu, Carlos ; D'Santos, Clive ; Taylor, Chris ; Qureshi, Arham ; Zecchini, Vincent R. ; Shaw, Greg L. ; Dehm, Scott M. ; Mills, Ian G. ; Carroll, James S. ; Tilley, Wayne D. ; McEwan, Iain J. ; Baniahmad, Aria ; Neal, David E. ; Asim, Mohammad. / A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer. In: Oncogene. 2019 ; Vol. 38, No. 7. pp. 1136-1150.
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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.",
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.",
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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 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

Y1 - 2019

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.

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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

U2 - 10.1038/s41388-018-0501-z

DO - 10.1038/s41388-018-0501-z

M3 - Article

VL - 38

SP - 1136

EP - 1150

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 7

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