St Andrews Research Repository

St Andrews University Home
View Item 
  •   St Andrews Research Repository
  • University of St Andrews Research
  • University of St Andrews Research
  • University of St Andrews Research
  • View Item
  •   St Andrews Research Repository
  • University of St Andrews Research
  • University of St Andrews Research
  • University of St Andrews Research
  • View Item
  •   St Andrews Research Repository
  • University of St Andrews Research
  • University of St Andrews Research
  • University of St Andrews Research
  • View Item
  • Login
JavaScript is disabled for your browser. Some features of this site may not work without it.

Cholinekinase alpha as an androgen receptor chaperone and prostate cancer therapeutic target

Thumbnail
View/Open
Lynch_2016_JNCI_CholineKinaseAlpha_CC.pdf (13.89Mb)
Date
01/05/2016
Author
Asim, Mohammad
Massie, Charles E.
Orafidiya, Folake
Pértega-Gomes, Nelma
Warren, Anne Y.
Esmaeili, Mohsen
Selth, Luke A.
Zecchini, Heather I.
Luko, Katarina
Qureshi, Arham
Baridi, Ajoeb
Menon, Suraj
Madhu, Basetti
Escriu, Carlos
Lyons, Scott
Vowler, Sarah L.
Zecchini, Vincent R.
Shaw, Greg
Hessenkemper, Wiebke
Russell, Roslin
Mohammed, Hisham
Stefanos, Niki
Lynch, Andy G.
Grigorenko, Elena
D’Santos, Clive
Taylor, Chris
Lamb, Alastair
Sriranjan, Rouchelle
Yang, Jiali
Stark, Rory
Dehm, Scott M.
Rennie, Paul S.
Carroll, Jason S.
Griffiths, John R.
Tavaré, Simon
Mills, Ian G.
McEwan, Iain J.
Baniahmad, Aria
Tilley, Wayne D.
Neal, David E.
Keywords
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
QH301 Biology
QH426 Genetics
DAS
Metadata
Show full item record
Altmetrics Handle Statistics
Altmetrics DOI Statistics
Abstract
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.
Citation
Asim , M , Massie , C E , Orafidiya , F , Pértega-Gomes , N , Warren , A Y , Esmaeili , M , Selth , L A , Zecchini , H I , Luko , K , Qureshi , A , Baridi , A , Menon , S , Madhu , B , Escriu , C , Lyons , S , Vowler , S L , Zecchini , V R , Shaw , G , Hessenkemper , W , Russell , R , Mohammed , H , Stefanos , N , Lynch , A G , Grigorenko , E , D’Santos , C , Taylor , C , Lamb , A , Sriranjan , R , Yang , J , Stark , R , Dehm , S M , Rennie , P S , Carroll , J S , Griffiths , J R , Tavaré , S , Mills , I G , McEwan , I J , Baniahmad , A , Tilley , W D & Neal , D E 2016 , ' Cholinekinase alpha as an androgen receptor chaperone and prostate cancer therapeutic target ' , Journal of the National Cancer Institute , vol. 108 , no. 5 , djv371 . https://doi.org/10.1093/jnci/djv371
Publication
Journal of the National Cancer Institute
Status
Peer reviewed
DOI
https://doi.org/10.1093/jnci/djv371
ISSN
0027-8874
Type
Journal article
Rights
© The Author 2015. Published by Oxford University Press. This is an 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.
Description
The RNA-seq data generated during this work has been submitted to Gene Expression Omnibus and is available for viewing at the following link http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token = ytazouoixxedjal&acc=GSE63700.
Collections
  • University of St Andrews Research
URL
https://academic.oup.com/jnci/article/2412425/Choline-Kinase-Alpha-as-an-Androgen-Receptor#supplementary-data
URI
http://hdl.handle.net/10023/11481

Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.

Advanced Search

Browse

All of RepositoryCommunities & CollectionsBy Issue DateNamesTitlesSubjectsClassificationTypeFunderThis CollectionBy Issue DateNamesTitlesSubjectsClassificationTypeFunder

My Account

Login

Open Access

To find out how you can benefit from open access to research, see our library web pages and Open Access blog. For open access help contact: openaccess@st-andrews.ac.uk.

Accessibility

Read our Accessibility statement.

How to submit research papers

The full text of research papers can be submitted to the repository via Pure, the University's research information system. For help see our guide: How to deposit in Pure.

Electronic thesis deposit

Help with deposit.

Repository help

For repository help contact: Digital-Repository@st-andrews.ac.uk.

Give Feedback

Cookie policy

This site may use cookies. Please see Terms and Conditions.

Usage statistics

COUNTER-compliant statistics on downloads from the repository are available from the IRUS-UK Service. Contact us for information.

© University of St Andrews Library

University of St Andrews is a charity registered in Scotland, No SC013532.

  • Facebook
  • Twitter