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dc.contributor.authorAsim, Mohammad
dc.contributor.authorMassie, Charles E.
dc.contributor.authorOrafidiya, Folake
dc.contributor.authorPértega-Gomes, Nelma
dc.contributor.authorWarren, Anne Y.
dc.contributor.authorEsmaeili, Mohsen
dc.contributor.authorSelth, Luke A.
dc.contributor.authorZecchini, Heather I.
dc.contributor.authorLuko, Katarina
dc.contributor.authorQureshi, Arham
dc.contributor.authorBaridi, Ajoeb
dc.contributor.authorMenon, Suraj
dc.contributor.authorMadhu, Basetti
dc.contributor.authorEscriu, Carlos
dc.contributor.authorLyons, Scott
dc.contributor.authorVowler, Sarah L.
dc.contributor.authorZecchini, Vincent R.
dc.contributor.authorShaw, Greg
dc.contributor.authorHessenkemper, Wiebke
dc.contributor.authorRussell, Roslin
dc.contributor.authorMohammed, Hisham
dc.contributor.authorStefanos, Niki
dc.contributor.authorLynch, Andy G.
dc.contributor.authorGrigorenko, Elena
dc.contributor.authorD’Santos, Clive
dc.contributor.authorTaylor, Chris
dc.contributor.authorLamb, Alastair
dc.contributor.authorSriranjan, Rouchelle
dc.contributor.authorYang, Jiali
dc.contributor.authorStark, Rory
dc.contributor.authorDehm, Scott M.
dc.contributor.authorRennie, Paul S.
dc.contributor.authorCarroll, Jason S.
dc.contributor.authorGriffiths, John R.
dc.contributor.authorTavaré, Simon
dc.contributor.authorMills, Ian G.
dc.contributor.authorMcEwan, Iain J.
dc.contributor.authorBaniahmad, Aria
dc.contributor.authorTilley, Wayne D.
dc.contributor.authorNeal, David E.
dc.date.accessioned2017-08-15T16:30:09Z
dc.date.available2017-08-15T16:30:09Z
dc.date.issued2016-05-01
dc.identifier.citationAsim , 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/djv371en
dc.identifier.issn0027-8874
dc.identifier.otherPURE: 250828093
dc.identifier.otherPURE UUID: 29db11e3-894c-4416-b763-7acd1dedad05
dc.identifier.otherRIS: urn:21BA2496937AF3DEA6918D55EF469FAC
dc.identifier.otherScopus: 84968909773
dc.identifier.otherORCID: /0000-0002-7876-7338/work/36106407
dc.identifier.urihttp://hdl.handle.net/10023/11481
dc.descriptionThe 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.en
dc.description.abstractBackground:  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.
dc.language.isoeng
dc.relation.ispartofJournal of the National Cancer Instituteen
dc.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.en
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectQH301 Biologyen
dc.subjectQH426 Geneticsen
dc.subjectDASen
dc.subject.lccRC0254en
dc.subject.lccQH301en
dc.subject.lccQH426en
dc.titleCholinekinase alpha as an androgen receptor chaperone and prostate cancer therapeutic targeten
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Statisticsen
dc.identifier.doihttps://doi.org/10.1093/jnci/djv371
dc.description.statusPeer revieweden
dc.identifier.urlhttps://academic.oup.com/jnci/article/2412425/Choline-Kinase-Alpha-as-an-Androgen-Receptor#supplementary-dataen


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