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

Key Points

  • 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.

Abstract

Forkhead box (Fox) proteins are a superfamily of evolutionarily conserved transcriptional regulators, which control a wide spectrum of biological processes. As a consequence, a loss or gain of Fox function can alter cell fate and promote tumorigenesis as well as cancer progression. Here we discuss the evidence that the deregulation of Fox family transcription factors has a crucial role in the development and progression of cancer, and evaluate the emerging role of Fox proteins as direct and indirect targets for therapeutic intervention, as well as biomarkers for predicting and monitoring treatment responses.

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Figure 1: Phylogenetic tree showing Fox proteins.
Figure 2: Post-translational regulation of Fox factors.

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Acknowledgements

S.M. is a research fellow supported by Cancer Research UK, and E.W.-F.L. is supported by grants from Cancer Research UK, the Leukaemia Research Fund, the Association for International Cancer Research and the Biotechnology and Biological Sciences Research Council.

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Glossary

Mitotic spindle

A component of the eukaryotic cytoskeleton that is required for chromosome segregation during mitosis. During spindle assembly in prometaphase, spindle microtubules attach to the kinetochore, a multiprotein complex that assembles on centromeric DNA, and chromosomes are pulled into alignment along the spindle midzone to form the metaphase spindle. Inaccurate chromosome segregation leads to aneuploidy, which may be associated with tumorigenesis.

Haemangiomas

Vascular tumours that are often visible as a red skin lesion owing to abnormal build up of blood vessels in the skin or internal organs.

TRegs

A subset of CD4+CD25+ regulatory T cells that control the responses of other T cells and tolerance to self antigens, which are referred to as naturally occurring regulatory T cells (TReg cells). TRegs are characterized by the expression of CD25 and FOXP3, and can suppress the activation of other T cells in a contact-dependent manner.

Compound heterozygote

Two different abnormal alleles at one locus, one on each chromosome of a pair.

Alveolar rhabdomyosarcoma

A paediatric soft tissue cancer related to the striated muscle lineage and characterized by the chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) leading to juxtaposition of PAX and FoxO family members.

Promyelocytic leukaemia (PML) nuclear bodies

Protein complexes that associate with the nuclear matrix and form the scaffold component of nuclear bodies. Many of the recruited proteins are involved in apoptosis control, and may also be directly involved in apoptosis and senescence. The formation of PML nuclear bodies may be modulated by a range of stress-related signalling pathways.

Oxidative stress

An excess of reactive oxygen species (ROS), caused by an imbalance between the rate of reduction and oxidation of oxygen, leading to free radical generation and damage to cellular components such as DNA and lipids. Manganese-containing superoxide dismutase (MnSOD), which is located within the mitochondrial matrix, facilitates the dismutation of the superoxide radicals to H202, and catalase is responsible for the oxidation of oxygen from H202 to H20. GADD45, which is induced by environmental stress and DNA damage, activates the stress kinase pathway, stimulates DNA excision repair, and inhibits entry of cells into S phase.

Quiescence

A period throughout which the cell does not divide. Relative quiescence is a defining characteristic of haematopoietic stem cells; in contrast to the rapid proliferation and terminal differentiation of their progeny. Stem cell quiescence is crucial in protecting the stem cell compartment.

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Myatt, S., Lam, EF. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 7, 847–859 (2007). https://doi.org/10.1038/nrc2223

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