title: Modeling truncated AR expression in a natural androgen responsive environment and identification of RHOB as a direct transcriptional target.
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.
authors.affiliation: Department of Biochemistry & Molecular Medicine, School of Medicine and Cancer Center, University of California Davis, Davis, CA, USA.
authors.forename: Hui-Chi
authors.initials: HC
authors.lastname: Tsai
authors.forename: David L
authors.initials: DL
authors.lastname: Boucher
authors.forename: Anthony
authors.initials: A
authors.lastname: Martinez
authors.forename: Clifford G
authors.initials: CG
authors.lastname: Tepper
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
mesh_terms: D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D020218:Response Elements; D014158:Transcription, Genetic; D020743:rhoB GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000728:Androgens; D002843:Chromatin; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D020743:rhoB GTP-Binding Protein; D004318:Doxycycline