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 journalArticlepeer-review

16 Citations (Scopus)
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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
Issue number7
Early online date20 Sept 2018
Publication statusPublished - Sept 2019

Bibliographical 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.


  • prostate cancer
  • androgen receptor
  • signalling kinase
  • transcriptional regulation
  • TOPK
  • GENE


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