Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer

• Published in: The EMBO journal 2011-10, Vol.30 (19), p.3962-3976
• Main Authors: Sahu, Biswajyoti, Laakso, Marko, Ovaska, Kristian, Mirtti, Tuomas, Lundin, Johan, Rannikko, Antti, Sankila, Anna, Turunen, Juha-Pekka, Lundin, Mikael, Konsti, Juho, Vesterinen, Tiina, Nordling, Stig, Kallioniemi, Olli, Hautaniemi, Sampsa, Jänne, Olli A
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; androgen receptor; Androgens; Androgens - metabolism; Binding sites; Cell Line, Tumor; Chromatin; Chromatin - metabolism; chromatin marks; Depletion; EMBO09; EMBO24; EMBO37; Female; Gene Expression Regulation, Neoplastic; glucocorticoid receptor; Glucocorticoids - metabolism; Hepatocyte Nuclear Factor 3-alpha - metabolism; Humans; Male; Molecular biology; Mortality; pioneer factor; Prostate cancer; Prostatic Neoplasms - metabolism; Protein Binding; Receptors, Estrogen - metabolism; Receptors, Glucocorticoid - metabolism; Signal Transduction; transcription programme; Transcription, Genetic; Tumors
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.328

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. Combining ChIP‐seq, bioinformatic and functional data, this study addresses the genome‐wide properties of the androgen receptor (AR). Modulation of the AR‐pioneering factor FoxA1 results in a new picture distinguishing FoxA1‐dependent from FoxA1‐independent AR‐genomic loci and the discovery of a third class that becomes reprogrammed by FoxA1 depletion.