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.
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Author contributions M.A. conceived the idea, designed the experiments, analysed the data, wrote the paper with input from all authors and oversaw the project. A.Y.W., B.S.C. and W.Z. performed IHC analysis. C.E.M. and S.M. performed bioinformatics analysis. T.P., K. W., K.L., F.O., C.E. and A.Q. performed experiments and analysed data. L.A.S., H.M., A. Baridi, C.D., X.Y., C.H., V.R.Z. analysed data, G.L.S., S.M.D., I.G.M., J.S.C., W.D.T., I.J.M. and A. Baniahmad provided reagents/advice. D.E.N. oversaw the project.Funding infor-mationWe 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 programme grant (to D.E.N.) and funding from the US Department of Defence (Prostate Cancer Research Program Transformative Impact Award, grant ID W81XWH-13-2-0093; W.D. T., S.M.D. and L.A.S.), National Health and medical Research Council (grant ID 1083961; L.A.S.) and PCFA/Cancer Australia/ Movember (grant IDs 1012337 and 1043482; W.D.T. and L.A.S.). The research programmes of W.D.T. and L.A.S. 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 S.M.D. F.O. was supported by a PhD project grant from Prostate Cancer UK (S10-10). M.A. was supported by a Young Investigator Award from the Prostate Cancer Foundation of the USA and a pump-priming grant from the University of Surrey, UK.
© 2018, The Author(s).