Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/118996
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Type: Journal article
Title: A reciprocal feedback between the PDZ binding kinase and androgen receptor drives prostate cancer
Author: Warren, A.
Massie, C.
Watt, K.
Luko, K.
Orafidiya, F.
Selth, L.
Mohammed, H.
Chohan, B.
Menon, S.
Baridi, A.
Zhao, W.
Escriu, C.
Pungsrinont, T.
D Santos, C.
Yang, X.
Taylor, C.
Qureshi, A.
Zecchini, V.
Shaw, G.
Dehm, S.
et al.
Citation: Oncogene, 2019; 38(7):1136-1150
Publisher: Springer Nature Publishing
Issue Date: 2019
ISSN: 0950-9232
1476-5594
Statement of
Responsibility: 
Anne Y. Warren, Charlie E. Massie, Kate Watt, Katarina Luko ... Luke A. Selth ... Wayne D. Tilley ... et al.
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.
Keywords: Cell Line, Tumor
Humans
Prostatic Neoplasms
Neoplasm Invasiveness
Neoplasm Metastasis
Mitogen-Activated Protein Kinase Kinases
Neoplasm Proteins
Receptors, Androgen
Protein Kinase Inhibitors
Signal Transduction
Gene Expression Regulation
Male
Rights: © The Author(s) 2018. This article is published with open access. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI: 10.1038/s41388-018-0501-z
Appears in Collections:Aurora harvest 4
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