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.

GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility

“…This resembles our observations for GATA3 and its ability to both positively and negatively impact ESR1 recruitment in breast cancer cells. A distinct difference is that in breast cancer cells lacking GATA3, we observed substantial epigenetic changes at distal enhancers, whereas in the prostate cells, enhancer accessibility was not affected when FOXA1 was silenced (Sahu et al 2011;Wang et al 2011). In general, forkhead and GATA members appear to facilitate nuclear receptor access to their DNA response elements.…”

Peroxisome Proliferator-Activated Receptor γ and C/EBPα Synergistically Activate Key Metabolic Adipocyte Genes by Assisted Loading

“…More recent genome-wide profiling of transcription factor binding combined with loss-of-function analyses has revealed that some transcription factors act as pioneer factors for others (53,54). Thus, Forkhead box A1 (FoxA1) has been shown to function as a pioneer factor for the estrogen receptor (53,55,56) and the androgen receptor (55,(57)(58)(59), PU.1 has been shown to facilitate C/EBP␤ and LXR binding during macrophage development (40), and C/EBPs and AP-1 have been shown to facilitate glucocorticoid receptor (GR) binding in several different model systems (60)(61)(62)(63). The current study extends cooperative binding of transcription factors to the major regulators of adipocyte differentiation and demonstrates that they can act as mutual pioneer factors for each other.…”

Pioneer transcription factors shape the epigenetic landscape

“…In ER + breast cancer cells, ER binding requires FOXA1 at many binding sites showing the role of FOXA1 in driving hormone response of these tumors (90). Similarly, AR binding is also influenced by FOXA1; indeed some AR binding sites are lost in cells depleted of FOXA1; however many sites are also gained suggesting a more complex relationship of FOXA1 with AR than with ER (87,91). Also, FOXM1 is amplified in some breast cancers (92), in non-Hodgkin's lymphomas (93) or in malignant peripheral nerve sheath tumors (94).…”

“…And indeed, FOX family genes are involved in several cancers (reviewed in (86). Overexpression of Foxa1 is associated with a poor prognosis in prostate cancer (87) while it is generally a good prognosis of breast cancer (88). Point mutations of FOXA1 were also found in some prostate cancers and this was associated with decreased androgen signaling and increased tumor growth (89).…”