FOXO transcription factors as therapeutic targets in human diseases

Abstract

Forkhead box (FOX)O proteins are transcription factors (TFs) with four members in mammals designated FOXO1, FOXO3, FOXO4, and FOXO6. FOXO TFs play a pivotal role in the cellular adaptation to diverse stress conditions. FOXO proteins act as context-dependent tumor suppressors and their dysregulation has been implicated in several age-related diseases. FOXO3 has been established as a major gene for human longevity. Accordingly, FOXO proteins have emerged as potential targets for the therapeutic development of drugs and geroprotectors. In this review, we provide an overview of the most recent advances in our understanding of FOXO regulation and function in various pathological conditions. We discuss strategies targeting FOXOs directly or by the modulation of upstream regulators, shedding light on the most promising intervention points. We also reveal the most relevant clinical indications and discuss the potential, trends, and challenges of modulating FOXO activity for therapeutic purposes.

Keywords: FOXO transcription factors; aging; cancer; cardiovascular and neurodegenerative diseases; diabetes; drugs and geroprotectors.

Figure 1.. Different levels of possible therapeutic interventions.

A. Posttranslational modification of FOXO proteins and their biological consequences. B. Pharmaceutical modulators can directly bind to the FOXO proteins and stabilize their interaction with DNA or disrupt the interaction of these proteins with other proteins of with their DNA binding site. Pharmacological intervention might also lead to increased or descresead transcription or the de/stabilization of FOXO transcripts. Drugs that inhibit enzymes that directly modify FOXO proteins or the upstream regulators of these enzymes might increase or decrese FOXO activity depending on the effect of the posttranslational modification. C. Small molecule compounds that directly bind to FOXO proteins to modulate FOXO functions. 1, AS1842856; 2, carbenoxolone; 3, repaglinide; 4, S9 and 5 tanzawaic acid D.

Figure 2.. Regulation and functions of FOXO in cardiovascular diseases.

Several cellular stimuli modulate FOXO activity and function through post-translational modifications of these proteins (phosphorylation-dephosphorylation, and acetylation-deacetylation, for example). The PI3K/AKT pathway promotes the phosphorylation and translocation/sequestration of FOXO1 in the cytoplasm. Several SIRT proteins deacetylate FOXO factors and promote their nuclear localization. Activated nuclear FOXO factors bind to specific FOXO-binding siteS and modulate the transcription of genes involved in autophagy, apoptosis, oxidative stress, hypertrophy, among others. The dysregulation of these FOXO targetS may lead to alteration of heart structure, function, metabolism, and cardiomyocyte dysfunction and death. Drugs acting through modulation of FOXO factors in the cardiovascular system areindicated in blue. P, indicates phosphorylation, and Ac, acetylation.

Figure 3.. Targeting FOXO protein levels by using exosomes containing circFoxo3 and/or cell-cycle regulators

A. Intron-exon structures of FOXO3. CircFoxo3 is formed from exon 3 (seond coding exonof FOXO3. B. Targeting specific cells with exosomes containing circFoxo3 would modulate miRNA levels, and protein levels, by competitive binding (i.e. sponging) of miRNAs. For example, upregulated circFOXO3 in prostate tissues can regulate the expression of SLC25A15, a mitochondrial metabolite transporter, by sponging miR-29a-3p, reversing its presumed tumor-suppressing roles [95]. circFOXO3 can also bind to RNA-binding proteins that regulate cell-cycle arrest, apoptosis, or growth. Therefore, exosomes containing circFoxo3 could result in modifications to 1) half-life of mRNA, 2) cell cycle arrest, 3) apoptosis, and/or 4) cell growth. C. Platforms for targeted degradation and stabilization of TFs of interest. Left panel, TF-DUBTACs; right panel TF-PROTACs. Figures C created with BioRender.com.

Box Figure I.. Domain structure of FOXO proteins.

FOXOs share a forkhead box DNA-binding domain (FH), a nuclear localization signal (NLS), a nuclear export signal (NES), a transactivation domain (TAD) and three conserved regions (CR), CR41, CR2 and CR3. FOXO6 lacks a functional NES.