Mp37-02 erg/akr1c3/ar constitutes a feed-forward loop for ar signaling in prostate cancer cells

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2015MP37-02 ERG/AKR1C3/AR CONSTITUTES A FEED-FORWARD LOOP FOR AR SIGNALING IN PROSTATE CANCER CELLS Katelyn Powell, Louie Semaan, Mary Conley-LaComb, Irfan Asangani, Yi-Mi Wu, Julia Williams, Jeremy Squire, Krishna Maddipati, Michael Cher, and Sreenivasa Chinni Katelyn PowellKatelyn Powell More articles by this author , Louie SemaanLouie Semaan More articles by this author , Mary Conley-LaCombMary Conley-LaComb More articles by this author , Irfan AsanganiIrfan Asangani More articles by this author , Yi-Mi WuYi-Mi Wu More articles by this author , Julia WilliamsJulia Williams More articles by this author , Jeremy SquireJeremy Squire More articles by this author , Krishna MaddipatiKrishna Maddipati More articles by this author , Michael CherMichael Cher More articles by this author , and Sreenivasa ChinniSreenivasa Chinni More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1265AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Intratumoral androgen synthesis in prostate cancer (PCa) contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus contributing to tumor growth in a castrate environment. The TMPRSS2-ERG transcription factor has been shown to be present in primary PCa tissue as well as CRPC tissue. We hypothesized that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene expression and the production of androgens, which contributes to the development of CRPC. METHODS We used a panel of assays including lentivirus transduction, gene expression, chromatin immunoprecipitation and sequencing, liquid chromatography-mass spectrometric quantitation, immunocytochemistry, immunohistochemistry and bio-informatics analysis of gene microarray databases to study ERG regulation of androgen synthesis in PCa. RESULTS We found that ERG regulated the expression of the ABE AKR1C3 in PCa cells via direct binding to the AKR1C3 gene. Knockdown of ERG resulted in reduced AKR1C3 expression, which caused a reduction in both dihydrotestosterone (DHT) synthesis and PSA expression in VCaP PCa cells treated with the DHT precursor metabolite 5α-androstanedione. Immunohistochemical staining revealed that ERG was co-expressed with AKR1C3 in PCa tissue samples. CONCLUSIONS These data suggest that AKR1C3 catalyzes the biochemical reduction of 5α-Androstanedione to DHT in PCa cells, and that ERG regulates this step through upregulation of AKR1C3 expression. Elucidation of ERG regulation of ABEs in CRPC may help to stratify TMPRSS2-ERG fusion-positive PCa patients in the clinic for anti-AR driven therapies; furthermore, AKR1C3 may serve as a valuable therapeutic target in the treatment of CRPC. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e438 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Katelyn Powell More articles by this author Louie Semaan More articles by this author Mary Conley-LaComb More articles by this author Irfan Asangani More articles by this author Yi-Mi Wu More articles by this author Julia Williams More articles by this author Jeremy Squire More articles by this author Krishna Maddipati More articles by this author Michael Cher More articles by this author Sreenivasa Chinni More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...