Therapeutic strategies targeting FOXO transcription factors

Abstract

FOXO proteins are transcription factors that are involved in numerous physiological processes and in various pathological conditions, including cardiovascular disease, cancer, diabetes and chronic neurological diseases. For example, FOXO proteins are context-dependent tumour suppressors that are frequently inactivated in human cancers, and FOXO3 is the second most replicated gene associated with extreme human longevity. Therefore, pharmacological manipulation of FOXO proteins is a promising approach to developing therapeutics for cancer and for healthy ageing. In this Review, we overview the role of FOXO proteins in health and disease and discuss the pharmacological approaches to modulate FOXO function.

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Fig. 1: Overview of FOXO post-translational modifications.
Fig. 2: Selected compounds that modulate FOXO activity and their targets.
Fig. 3: Chemical structures of selected compounds identified to be modulators of FOXO activity.

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Acknowledgements

This work was supported by the Spanish Ministry of Science, Innovation and Universities through Grant RTI2018-094629-B-I00 and by the European commission (INTERREG VA POCTEP-055 ALGARED_PLUS_5E) to W.L. E.W.-F.L.’s work is supported by MRC (MR/N012097/1), CRUK (C37/A12011) and Breast Cancer Now (2012MayPR070; 2012NovPhD016; 2014NovPhD326).

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Correspondence to Wolfgang Link.

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W.L. is scientific co-founder of a company and is required by his institution to state so in his publications. G.C. and E.W.-F.L. declare no competing interests.

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Glossary

Tissue homeostasis

A process that ensures the maintenance of an internal steady state of a specific tissue of an organism and includes the control of cell proliferation, cell death and metabolic functions.

Senolytics

A class of drugs that selectively clears senescent cells, which are one of the hallmarks of ageing. Senescent cells are non-responsive to growth-promoting stimuli and are therefore unable to re-enter the cell cycle.

Transactivation domain

(TAD). A protein domain present in many transcription factors that contain binding sites for regulatory proteins, such as transcriptional co-repressors or co-activators.

DAF-16 binding element

A DNA regulatory element with the consensus sequence 5′-GTAAACAA-3′ that binds to FOXO transcription factors and is involved in the regulation of FOXO target gene expression. It is named after the FOXO orthologue in Caenorhabditis elegans, Daf-16.

Insulin-responsive element

A DNA regulatory element with the consensus sequence 5′-(C/A)(A/C)AAA(C/T)AA-3′ that is present in several gene promoters, including the insulin-like growth factor-binding protein promoter, and that is responsible for the insulin-mediated inhibition of transcription. Insulin-responsive elements can bind to members of the forkhead family of transcription factors.

Histone acetyltransferases

(HATs). A class of enzymes that transfer acetyl groups onto lysine residues of cellular proteins, including histones.

Histone deacetylases

(HDACs). A class of enzymes that remove acetyl groups from ε-amino groups on lysine residues of the amino-terminal tails of histones. They also deacetylate non-histone proteins.

Reactive oxygen species

(ROS). Oxygen-containing molecules with one or more unpaired electrons. ROS are free radicals that can cause damage to DNA, RNA and proteins. ROS-mediated damage has been implicated in ageing.

Nigral neurons

A collection of nerve cells that form the substantia nigra located in the midbrain. The name is based on the dark colour of the cells due to the presence of neuromelanin. These neurons produce dopamine and their loss leads to the motor deficits observed in Parkinson disease.

Embryonic stem cells

Stem cells isolated from the inner cell mass of an embryo at a very early developmental stage when they are able to give rise to any cell type of the body.

Induced pluripotent stem cells

Pluripotent stem cells derived from adult somatic cells through reprogramming by inducing genes. They resemble embryonic stem cells in many aspects.

β-cells

Cells found in the islets of Langerhans of the pancreas and responsible for the production of insulin. The number of β-cells is decreased in patients with type I diabetes, resulting in insufficient insulin secretion and hyperglycaemia.

Cardiac hypertrophy

An increase in cardiac muscle mass that occurs as an adaptive response to physiological or pathophysiological events and results from increased cardiomyocyte size and alterations in other heart muscle components. This condition most commonly affects the left ventricle and is associated with many forms of heart disease.

Fetal haemoglobin

A haemoglobin variant that predominates during fetal life and in the blood of a newborn, which binds to oxygen more strongly than to adult haemoglobin, allowing for the prenatal transfer of oxygen from mother to fetus. While adult haemoglobin is composed of two α-subunits and two β-subunits, fetal haemoglobin is composed of two α-subunits and two γ-subunits.

Nucleus pulposus

The soft, gelatinous, inner core of the vertebral disc, which is an elastic structure consisting of water and collagen fibres that allows the disc to resist compression and torsion. It can herniate, leaking out of the disc space and inflaming the nerve roots.

Cartilaginous endplates

Thin layers of hyaline cartilage that cover the top and bottom of intervertebral discs and provide structural support and regulate nutrient and metabolic exchange in the disc.

Dietary restriction

A dietary regimen, also referred to as caloric restriction, that reduces calorie intake without incurring malnutrition and has been shown to delay ageing in several model organisms.

Single-nucleotide polymorphisms

(SNPs). A DNA sequence variation in the genome of members of a species or between paired chromosomes in an individual that consists of the alteration of a single nucleotide. While mutations are a rare sequence variation, SNPs are present in more than 1% of a population.

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Calissi, G., Lam, E.WF. & Link, W. Therapeutic strategies targeting FOXO transcription factors. Nat Rev Drug Discov 20, 21–38 (2021). https://doi.org/10.1038/s41573-020-0088-2

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