title: Cell-lineage specificity and role of AP-1 in the prostate fibroblast androgen receptor cistrome.
abstract: Androgen receptor (AR) signalling in fibroblasts is important in prostate development and carcinogenesis, and is inversely related to prostate cancer mortality. However, the molecular mechanisms of AR action in fibroblasts and other non-epithelial cell types are largely unknown. The genome-wide DNA binding profile of AR in human prostate fibroblasts was identified by chromatin immunoprecipitation sequencing (ChIP-Seq), and found to be common to other fibroblast lines but disparate from AR cistromes of prostate cancer cells and tissue. Although AR binding sites specific to fibroblasts were less well conserved evolutionarily than those shared with cancer epithelia, they were likewise correlated with androgen regulation of fibroblast gene expression. Whereas FOXA1 is the key pioneer factor of AR in cancer epithelia, our data indicated that AP-1 likely plays a more important role in the AR cistrome in fibroblasts. The specificity of AP-1 and FOXA1 to binding in these cells is demonstrated using immunoblot and immunohistochemistry. Importantly, we find the fibroblast cistrome is represented in whole tissue/in vivo ChIP-seq studies at both genomic and resulting protein levels, highlighting the importance of the stroma in whole tissue -omic studies. This is the first nuclear receptor ChIP-seq study in prostatic fibroblasts, and provides novel insight into the action of fibroblast AR in prostate cancer.
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, The University of Adelaide, SA, Australia; Department of Surgery and Cancer, Imperial College London, United Kingdom.
authors.forename: Damien A
authors.initials: DA
authors.lastname: Leach
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, The University of Adelaide, SA, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Panagopoulos
authors.affiliation: Division of Urology, Department of Surgery, McGill University Health Centre, Montreal, Canada.
authors.forename: Claire
authors.initials: C
authors.lastname: Nash
authors.affiliation: Department of Surgery and Cancer, Imperial College London, United Kingdom.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bevan
authors.affiliation: Division of Urology, Department of Surgery, McGill University Health Centre, Montreal, Canada.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Thomson
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, Adelaide, SA, Australia; Freemasons Foundation Centre for Mens' Health, School of Medicine, The University of Adelaide, Adelaide, SA, Australia. Electronic address: luke.selth@adelaide.edu.au.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Selth
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, The University of Adelaide, SA, Australia. Electronic address: grant.buchanan@adelaide.edu.au.
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D005347:Fibroblasts / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D008297:Male; D011467:Prostate / Q000166:cytology*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D019098:Telomerase / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D002843:Chromatin; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D011944:Receptors, Androgen; D018808:Transcription Factor AP-1; D019098:Telomerase
keywords: Androgen receptor; Chromatin immunoprecipitation; Fibroblasts; Prostate cancer; Stroma