Department of Pathology, Addenbrooke's Cambridge University Hospital, Cambridge, UK.
Early Detection Programme, Cancer Research UK Cambridge Centre, Department of Oncology, University of Cambridge, Cambridge, UK.
Oncogene. 2019 Feb;38(7):1136-1150. doi: 10.1038/s41388-018-0501-z. Epub 2018 Sep 20.
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.
阐明导致雄激素受体 (AR) 活性增加以及随后侵袭性前列腺癌 (PrCa) 发展的机制，对于开发新的治疗方法至关重要。我们采用系统生物学方法研究了 AR 调控的蛋白质组，发现 PDZ 结合激酶 (PBK) 是一种新的 AR 调控蛋白，可调节 PrCa 中全长 AR 和 AR 变体 (ARV) 的活性。在侵袭性 PrCa 中 PBK 的过表达与早期生化复发和不良临床结局相关。除了其羧基末端配体结合结构域外，PBK 还直接与 AR 的氨基末端反式激活结构域相互作用，从而稳定 AR，导致在 PrCa 中观察到的 AR 蛋白表达增加。转录组测序显示，PBK 是全球 AR 信号的介导物，在调节肿瘤侵袭和转移方面发挥关键作用。PBK 抑制减少了 PrCa 细胞系和离体培养的临床标本的生长。我们揭示了 AR 和 PBK 之间的一种新相互作用，导致 AR 和 ARV 的表达增加，从而执行 AR 介导的 PrCa 的生长和进展，这对开发用于治疗侵袭性 PrCa 的 PBK 抑制剂具有重要意义。
