BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.
METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.
RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.
CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.
This work was supported by a Cancer Research UK program
grant (to DEN) and also by the US Department of Defense
(Prostate Cancer Research Program Transformative Impact
Award, grant ID W81XWH-13-2-0093 to WDT and SMD), PCFA/
Cancer Australia/Movember (grant IDs 1012337 and 1043482
to WDT and LAS), Cancer Australia (grant ID 1043497 to WDT
and JC), and The Ray and Shirl Norman Cancer Research Trust
(to WDT and LAS). The Dame Roma Mitchell Cancer Research
Laboratories were supported by an establishment grant from
the Prostate Cancer Foundation Australia (ID 2011/0452). FO was
supported by a PhD project grant from Prostate Cancer UK (S10-
10). LAS is supported by a Young Investigator Award from the
Prostate Cancer Foundation (the Foundation 14 award).
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- School of Medicine, Medical Sciences & Nutrition, Molecular and Cellular Function
- School of Medicine, Medical Sciences & Nutrition, Aberdeen Cancer Centre
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Personal Chair
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences