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.
|Number of pages||15|
|Early online date||20 Sep 2018|
|Publication status||Published - Sep 2019|
- prostate cancer
- androgen receptor
- signalling kinase
- transcriptional regulation
- ORIGINATED PROTEIN-KINASE
- MITOTIC KINASE
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- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Personal Chair
- Institute of Medical Sciences