Modeling Truncated AR Expression in a Natural Androgen Responsive Environment and Identification of RHOB as a Direct Transcriptional Target

H.-C. Tsai, D.L. Boucher, A. Martinez, C.G. Tepper, H.-J. Kung

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9 Citations (Scopus)

Abstract

Recent studies identifying putative truncated androgen receptor isoforms with ligand-independent activity have shed new light on the acquisition of androgen depletion independent (ADI) growth of prostate cancer. In this study, we present a model system in which a C-terminally truncated variant of androgen receptor (TC-AR) is inducibly expressed in LNCaP, an androgen-dependent cell line, which expresses little truncated receptor. We observed that when TC-AR is overexpressed, the endogenous full length receptor (FL-AR) is transcriptionally downmodulated. This in essence allows us to "replace" FL-AR with TC-AR and compare their individual properties in exactly the same genetic and cellular background, which has not been performed before. We show that the TC-AR translocates to the nucleus, activates transcription of AR target genes in the absence of DHT and is sufficient to confer ADI growth to the normally androgen dependent LNCaP line. We also show that while there is significant overlap in the genes regulated by FL- and TC-AR there are also differences in the respective suites of target genes with each AR form regulating genes that the other does not. Among the genes uniquely activated by TC-AR is RHOB which is shown to be involved in the increased migration and morphological changes observed in LN/TC-AR, suggesting a role of RHOB in the regulation of androgen-independent behavior of prostate cancer cells. © 2012 Tsai et al.
Original languageEnglish
JournalPLoS One
Volume7
Issue number11
DOIs
Publication statusPublished - Nov 2012
Externally publishedYes

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Keywords

  • androgen receptor
  • doxycycline
  • heterodimer
  • messenger RNA
  • article
  • biological model
  • carboxy terminal sequence
  • cell migration
  • cell shape
  • cell strain LNCaP
  • controlled study
  • gene
  • gene activation
  • gene identification
  • gene silencing
  • gene targeting
  • genetic transcription
  • protein expression
  • protein function
  • protein localization
  • receptor down regulation
  • reverse transcription polymerase chain reaction
  • RHOB gene
  • transcription regulation
  • upregulation
  • Androgens
  • Cell Line, Tumor
  • Cell Movement
  • Cell Nucleus
  • Chromatin
  • Dihydrotestosterone
  • Doxycycline
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Prostatic Neoplasms
  • Protein Binding
  • Protein Multimerization
  • Protein Transport
  • Receptors, Androgen
  • Reproducibility of Results
  • Response Elements
  • rhoB GTP-Binding Protein
  • RNA, Messenger
  • Transcription, Genetic

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