title: Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer.
abstract: High androgen receptor (AR) level in primary tumour predicts increased prostate cancer-specific mortality. However, the mechanisms that regulate AR function in prostate cancer are poorly known. We report here a new paradigm for the forkhead protein FoxA1 action in androgen signalling. Besides pioneering the AR pathway, FoxA1 depletion elicited extensive redistribution of AR-binding sites (ARBs) on LNCaP-1F5 cell chromatin that was commensurate with changes in androgen-dependent gene expression signature. We identified three distinct classes of ARBs and androgen-responsive genes: (i) independent of FoxA1, (ii) pioneered by FoxA1 and (iii) masked by FoxA1 and functional upon FoxA1 depletion. FoxA1 depletion also reprogrammed AR binding in VCaP cells, and glucocorticoid receptor binding and glucocorticoid-dependent signalling in LNCaP-1F5 cells. Importantly, FoxA1 protein level in primary prostate tumour had significant association to disease outcome; high FoxA1 level was associated with poor prognosis, whereas low FoxA1 level, even in the presence of high AR expression, predicted good prognosis. The role of FoxA1 in androgen signalling and prostate cancer is distinctly different from that in oestrogen signalling and breast cancer.
authors.affiliation: Institute of Biomedicine, Physiology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Biswajyoti
authors.initials: B
authors.lastname: Sahu
authors.forename: Marko
authors.initials: M
authors.lastname: Laakso
authors.forename: Kristian
authors.initials: K
authors.lastname: Ovaska
authors.forename: Tuomas
authors.initials: T
authors.lastname: Mirtti
authors.forename: Johan
authors.initials: J
authors.lastname: Lundin
authors.forename: Antti
authors.initials: A
authors.lastname: Rannikko
authors.forename: Anna
authors.initials: A
authors.lastname: Sankila
authors.forename: Juha-Pekka
authors.initials: JP
authors.lastname: Turunen
authors.forename: Mikael
authors.initials: M
authors.lastname: Lundin
authors.forename: Juho
authors.initials: J
authors.lastname: Konsti
authors.forename: Tiina
authors.initials: T
authors.lastname: Vesterinen
authors.forename: Stig
authors.initials: S
authors.lastname: Nordling
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: Olli A
authors.initials: OA
authors.lastname: Jänne
mesh_terms: D020816:Amino Acid Motifs; D000728:Androgens / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005938:Glucocorticoids / Q000378:metabolism; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000728:Androgens; D002843:Chromatin; C496499:FOXA1 protein, human; D005938:Glucocorticoids; D051541:Hepatocyte Nuclear Factor 3-alpha; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid