The discrete roles of individual FOXO transcription factor family members in B-cell malignancies

Abstract

Forkhead box (FOX) class O (FOXO) proteins are a dynamic family of transcription factors composed of four family members: FOXO1, FOXO3, FOXO4 and FOXO6. As context-dependent transcriptional activators and repressors, the FOXO family regulates diverse cellular processes including cell cycle arrest, apoptosis, metabolism, longevity and cell fate determination. A central pathway responsible for negative regulation of FOXO activity is the phosphatidylinositol-3-kinase (PI3K)-AKT signalling pathway, enabling cell survival and proliferation. FOXO family members can be further regulated by distinct kinases, both positively (e.g., JNK, AMPK) and negatively (e.g., ERK-MAPK, CDK2), with additional post-translational modifications further impacting on FOXO activity. Evidence has suggested that FOXOs behave as ‘bona fide’ tumour suppressors, through transcriptional programmes regulating several cellular behaviours including cell cycle arrest and apoptosis. However, an alternative paradigm has emerged which indicates that FOXOs operate as mediators of cellular homeostasis and/or resistance in both ‘normal’ and pathophysiological scenarios. Distinct FOXO family members fulfil discrete roles during normal B cell maturation and function, and it is now clear that FOXOs are aberrantly expressed and mutated in discrete B-cell malignancies. While active FOXO function is generally associated with disease suppression in chronic lymphocytic leukemia for example, FOXO expression is associated with disease progression in diffuse large B cell lymphoma, an observation also seen in other cancers. The opposing functions of the FOXO family drives the debate about the circumstances in which FOXOs favour or hinder disease progression, and whether targeting FOXO-mediated processes would be effective in the treatment of B-cell malignancies. Here, we discuss the disparate roles of FOXO family members in B lineage cells, the regulatory events that influence FOXO function focusing mainly on post-translational modifications, and consider the potential for future development of therapies that target FOXO activity.

Non-coding variants impact cis-regulatory coordination in a cell type-specific manner

“…We observed enrichment of many similar types of TFs, related to B cell function such as IRF, RUNX, and EBF1 (Additional file 1 : Fig. S5.2e, f), but also specific enrichment of factors such as FOXO1 (as also seen for rs895555) in CLL which have been implicated in CLL and harbor driver mutations [ 75 ]. Despite the limited number of genotypes available for CLL, we show that CMs can be used to identify candidate variants associated with CLL.…”

“…The T allele of rs895555 creates the core of a putative Forkhead (FOX) TF binding site (( T /C)GTTT) (Additional file 1 : Fig. S5.1d), which is of interest given the implication of this TF family in the development and progression of B cell malignancies [ 75 ]. OSBPL5 expression is a prognostic marker for overall survival in the context of mutated immunoglobulin heavy variable (IGHV) gene status (Fig.…”

Opposing Interplay between Nuclear Factor Erythroid 2-Related Factor 2 and Forkhead BoxO 1/3 is Responsible for Sepantronium Bromide’s Poor Efficacy and Resistance in Cancer cells: Opportunity for Combination Therapy in Triple Negative Breast Cancer

“…Constitutively activated FoxO partially reduced cell survival in the YMR cells (Figure E). The incomplete effects of FoxO1 inhibition (with AS184256) or FoxO3 activation (with FOXO3TM) on YM155-mediated cell survival could be due their nonoverlapping target genes despite having core DNA-binding sequence . We repeated these experiments in another set of isogenic sensitive and YMR cell line pair derived from the MDA-MB-453 cells (Figure S3A, S3B, S3C).…”

“…The incomplete effects of FoxO1 inhibition (with AS184256) or FoxO3 activation (with FOXO3TM) on YM155-mediated cell survival could be due their nonoverlapping target genes despite having core DNA-binding sequence. 21 We repeated these experiments in another set of isogenic sensitive and YMR cell line pair derived from the MDA-MB-453 cells (Figure S3A, S3B, S3C). The survivin-suppressive function of YM155 was originally attributed to its interaction with Sp1 transcription factor which has several binding sites at the promoter region of the BIRC5 gene.…”

Mechanistic prediction and validation of Brevilin A Therapeutic effects in Lung Cancer

“…Additionally, CAF-derived exosomes have been identified to promote NSCLC cellular proliferation and chemoresistance through regulation of the PTEN/PI3K-AKT signaling axis [ 55 ]. The FOXO signaling pathway, triggered by the PI3K/AKT pathway, is instrumental in mediating cell proliferation, differentiation, and tumorigenesis [ 56 , 57 ]. Inhibition of CCCTC-binding factor (CTCF) has been shown to regulate the FoxO signaling pathway, impeding tumor growth in vivo [ 58 ].…”