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 languageEnglish
Pages (from-to)1136-1150
Number of pages15
JournalOncogene
Volume38
Early online date20 Sep 2018
DOIs
Publication statusPublished - 14 Feb 2019
Externally publishedYes

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Keywords

  • androgen receptor
  • prostate cancer

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    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