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.
Molecular and cellular endocrinology. 2016 Sep 12 [Epub ahead of print]
Damien A Leach, Vasilios Panagopoulos, Claire Nash, Charlotte Bevan, Axel A Thomson, Luke A Selth, Grant Buchanan
The Basil Hetzel Institute for Translational Health Research, The University of Adelaide, SA, Australia; Department of Surgery and Cancer, Imperial College London, United Kingdom., The Basil Hetzel Institute for Translational Health Research, The University of Adelaide, SA, Australia., Division of Urology, Department of Surgery, McGill University Health Centre, Montreal, Canada., Department of Surgery and Cancer, Imperial College London, United Kingdom., 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: ., The Basil Hetzel Institute for Translational Health Research, The University of Adelaide, SA, Australia. Electronic address: .