TY - JOUR
T1 - Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target
AU - Asim, Mohammad
AU - Massie, Charles E.
AU - Orafidiya, Folake
AU - Pértega-Gomes, Nelma
AU - Warren, Anne Y.
AU - Esmaeili, Mohsen
AU - Selth, Luke A.
AU - Zecchini, Heather I.
AU - Luko, Katarina
AU - Qureshi, Arham
AU - Baridi, Ajoeb
AU - Menon, Suraj
AU - Madhu, Basetti
AU - Escriu, Carlos
AU - Lyons, Scott
AU - Vowler, Sarah L.
AU - Zecchini, Vincent R.
AU - Shaw, Greg
AU - Hessenkemper, Wiebke
AU - Russell, Roslin
AU - Mohammed, Hisham
AU - Stefanos, Niki
AU - Lynch, Andy G.
AU - Grigorenko, Elena
AU - D'Santos, Clive
AU - Taylor, Chris
AU - Lamb, Alastair
AU - Sriranjan, Rouchelle
AU - Yang, Jiali
AU - Stark, Rory
AU - Dehm, Scott M.
AU - Rennie, Paul S.
AU - Carroll, Jason S.
AU - Griffiths, John R.
AU - Tavaré, Simon
AU - Mills, Ian G.
AU - McEwan, Iain J.
AU - Baniahmad, Aria
AU - Tilley, Wayne D.
AU - Neal, David E.
N1 - Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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 χ2 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.
AB - 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 χ2 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.
UR - http://www.scopus.com/inward/record.url?scp=84968909773&partnerID=8YFLogxK
U2 - 10.1093/jnci/djv371
DO - 10.1093/jnci/djv371
M3 - Article
C2 - 26657335
AN - SCOPUS:84968909773
SN - 0027-8874
VL - 108
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 5
M1 - djv371
ER -
