The emerging roles of forkhead box (Fox) proteins in cancer

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Abstract
Forkhead box (Fox) proteins are a superfamily of evolutionarily conserved transcriptional regulators, which are characterized by the forkhead DNA binding domains, and control a wide range of biological processes. Fox proteins can both activate and repress gene expression through the recruitment of co-factors or repressors, primarily histone deacetylases (HDACs). In addition, Fox proteins interact extensively with other factors such as p53 and oestrogen receptor to modulate gene expression, and deregulation of Fox protein activity or expression results in changes in both direct and indirect target genes. Fox proteins are largely deregulated through genetic events and alterations in post-translational modifications. Post-translational control of Fox protein activity is exerted through an intricate balance of phosphorylation, acetylation and mono-ubiquitylation that influences protein interactions and sub-cellular localization. Deregulation of Fox proteins is commonly associated with tumorigenesis and cancer progression; Fox proteins may be directly targeted or deregulated by mutations in upstream factors. Overexpression of FOXM1 promotes cell-cycle progression, and overexpression of FOXC2 promotes tumour metastasis and invasion. By contrast, loss of FOXO3A activity may increase resistance to apoptosis and cell-cycle progression, and deregulation of FoxP family members can result in tumour immune evasion. Fox proteins may act as both direct and indirect targets for therapeutic intervention. However, the complex nature of Fox transcription factor signalling and their roles as both tumour suppressors and oncogenes makes them challenging therapeutic targets.