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 for this work

Research output: Contribution to journalArticle

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

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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