title: Genome-wide analysis of androgen receptor binding and gene regulation in two CWR22-derived prostate cancer cell lines.
abstract: Prostate carcinoma (CaP) is a heterogeneous multifocal disease where gene expression and regulation are altered not only with disease progression but also between metastatic lesions. The androgen receptor (AR) regulates the growth of metastatic CaPs; however, sensitivity to androgen ablation is short lived, yielding to emergence of castrate-resistant CaP (CRCaP). CRCaP prostate cancers continue to express the AR, a pivotal prostate regulator, but it is not known whether the AR targets similar or different genes in different castrate-resistant cells. In this study, we investigated AR binding and AR-dependent transcription in two related castrate-resistant cell lines derived from androgen-dependent CWR22-relapsed tumors: CWR22Rv1 (Rv1) and CWR-R1 (R1). Expression microarray analysis revealed that R1 and Rv1 cells had significantly different gene expression profiles individually and in response to androgen. In contrast, AR chromatin immunoprecipitation (ChIP) combined with promoter DNA microarrays (ChIP-on-chip) studies showed that they have a similar AR-binding profile. Coupling of the microarray study with ChIP-on-chip analysis identified direct AR targets. The most prominent function of transcripts that were direct AR targets was transcriptional regulation, although only one transcriptional regulator, CCAAT/enhancer binding protein δ, was commonly regulated in both lines. Our results indicate that the AR regulates the expression of different transcripts in the two lines, and demonstrate the versatility of the AR-regulated gene expression program in prostate tumors.
authors.affiliation: Department of Medical Microbiology and Immunology, University of California Davis, Davis, California 95616, USA.
authors.forename: Honglin
authors.initials: H
authors.lastname: Chen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Libertini
authors.forename: Michael
authors.initials: M
authors.lastname: George
authors.forename: Satya
authors.initials: S
authors.lastname: Dandekar
authors.forename: Clifford G
authors.initials: CG
authors.lastname: Tepper
authors.forename: Bushra
authors.initials: B
authors.lastname: Al-Bataina
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.forename: Paramita M
authors.initials: PM
authors.lastname: Ghosh
authors.forename: Maria
authors.initials: M
authors.lastname: Mudryj
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D013196:Dihydrotestosterone / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
chemical_list: C410798:AR protein, human; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone