FOXO family in regulating cancer and metabolism

doi:10.1016/j.semcancer.2018.01.018

Seminars in Cancer Biology

Volume 50, June 2018, Pages 32-41

https://doi.org/10.1016/j.semcancer.2018.01.018 Get rights and content

Abstract

FOXO proteins are a sub-group of a superfamily of forkhead box (FOX)-containing transcription factors (TFs). FOXOs play an important role in regulating a plethora of biological activities ranging from development, cell signaling, and tumorigenesis to cell metabolism. Here we mainly focus on reviewing the role of FOXOs in regulating tumor and metabolism. Moreover, how crosstalk among various pathways influences the function of FOXOs will be reviewed. Further, the paradoxical role for FOXOs in controlling the fate of cancer and especially resistance/sensitivity of cancer to the class of drugs that target PI3K/AKT will also be reviewed. Finally, how FOXOs regulate crosstalk between common cancer pathways and cell metabolism pathways, and how these crosstalks affect the fate of the cancer will be discussed.

Introduction

FOXO proteins are a sub-group of a superfamily of forkhead box (FOX)-containing transcription factors (TFs). The founding member of this superfamily, dFOXO, was discovered as the gene whose mutation causes defective development of fruit fly (D. melanogaster), with an extra head (hence forkhead phenotype) [1]. A hallmark of this superfamily of proteins is that they contain a conserved protein domain, forkhead box (FOX), which consists of about 100 amino acid residues that directly bind DNA sequence in the enhancers of various target genes [2]. The FOX domain in the TFs binds DNA with a helix-turn-helix motif with two large loops (like wings), so earlier on these TFs were also referred to as winged helix/forkhead TFs [3]. As a growing number of the TFs with the conserved domain were identified from various species ranging from yeast to humans, surpassing 100, a necessity arose to systematically classify and name these TFs. Phylogenetic analysis of the sequences of the known chordate FOX proteins classifies these TFs into 19 subclasses, ranging from FOXA to FOXS [[3], [4]]. The structure and function of FOXO family of TFs have been excellently reviewed [[5], [6], [7]], and here we mainly focus on reviewing their key role in regulating cancer and the potential crosstalk between cancer and cell metabolism related signaling pathways.

Section snippets

FOXO family members

In invertebrates such as nematode C. elegans and the fruit fly, there is only one FOXO homologous gene, termed daf-16 in the worm and dFOXO in the fly. In mammals, four subfamily members have been identified: FOXO1 (previously also known as FKHR), FOXO3 (aka FKHRL1), FOXO4 (aka AFX) [8] and FOXO6. FOXO1, FOXO3 and FOXO4 mRNAs are expressed ubiquitously in varying levels in mammals [[9], [10]]. Expression of FOXOs has certain tissue preference. FOXO1 is highly expressed in adipose tissues, while

Genetic and biochemistry characters of FOXO proteins

The highly conserved DNA-binding forkhead box domain (∼100-amino-acid Forkhead box) is located in the N-terminal region of the protein, while the transactivation domain is located in the C-terminal region (Fig. 1). In addition, FOXOs except FOXO6 also contain nuclear export sequence and nuclear localization signals that are responsible for shuttling of FOXOs between the nucleus and cytoplasm [12]. FOXO6 lacks NES and its distribution is nuclear independent of external signaling [11]. FOXO

Regulation of FOXOs by PI3K/AKT

A prominent feature of FOXOs is that their cellular localization in the cytoplasm and nucleus is tightly regulated. There is a nuclear localization signal (NLS) domain and a nuclear export signal (NES) domain in FOXOs, facilitating the shuttling of FOXOs between the cytoplasm and the nucleus (Fig. 1). Certain cell signaling events, such as insulin signaling, changes the balance of their cellular distribution. On activation by the extracellular signals such as insulin or insulin-like growth

The role of FOXOs to suppress tumorigenesis

FOXOs have diverse functions and control various biological functions, including cell cycle arrest at the G₁-S [57] and G₂-M [58] checkpoints, detoxification of reactive oxygen species (ROS) [59], repair of damaged DNA [[58], [60]], and apoptosis [61]. It is well known that high expression or activation of FOXOs in cells is associated with anti-proliferation and apoptosis, functions related to tumor suppression. FOXO3 is well known for its role in repressing cell proliferation and its

Paradoxical role for FOXOs in controlling the fate of cancer

Although FOXOs are generally associated with suppressing cell proliferation and tumorigenesis, in certain conditions, FOXOs are also involved in driving or sustaining tumor cell growth or leading tumor cells to drug resistance. For instance, high expression of FOXO6 is positively correlated with the progression and poor prognosis of gastric cancer [67], and it promotes tumorigenicity via upregulation of C-Myc [65]. In lung cancer cells, inhibition of mutant EGFR triggers SOX2-FOXO6-dependent

FOXOs regulate cell metabolism in multiple organs

As potent effectors of the insulin signaling pathway, FOXOs are involved in the insulin pathway-regulated process of metabolism in different type cells or tissues. In liver, overexpression of FOXO1 inhibits the expression of genes involved in glycolysis, the pentose phosphate pathway and lipogenesis, resulting in increased glucose synthesis under fasting and insulin resistance [80]. Mice with FOXO1- deletion in the liver are resistant to high fat diet-induced insulin resistance [[81], [82]].

The role of FOXOs in regulating beta cells

The maintenance of beta cell function and mass is critical for glucose homeostasis. The previous studies have demonstrated that FOXO1 is involved in regulating beta cell mass and protecting beta cell function [[81], [97], [129], [130]].

The mechanism underlying the role of FOXOs in regulating different cancers

FOXOs are crucial factors for promoting or sustaining a subset of AML [73] and cause drug resistance in HER2+ breast cancer cells [[74], [139]]. Thus, it is interesting to understand whether this mechanism also applies to other types of cancers, especially HER2+ or other PI3 K/AKT pathway-augmented cancers. This is important because many types of cancers, directly or indirectly, harbors much enhanced PI3K/AKT pathways, and numerous efforts are made to develop new drugs to target these pathways

Conflict of interest

None.

Acknowledgements

We acknowledge that this work was supported in part by grants from the NIH (1-R01-CA-178856 and R01 DK097555), AACR-Neuroendocrine tumor research foundation (NETRF), a Harrington Discovery Institute Innovator Scholar award, a CTSA-ITMAT pilot grant at University of Pennsylvania, and an international postdoctoral exchange fellowship program from China Postdoctoral Science Foundation. We apologize for not being able to cite all the important publications due to space limitation.

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¹: Current address: Division of Oncology and Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia, 3501 Civic Center Blvd, Philadelphia, PA, 19104, USA.

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FOXO family in regulating cancer and metabolism

Abstract

Introduction

Section snippets

FOXO family members

Genetic and biochemistry characters of FOXO proteins

Regulation of FOXOs by PI3K/AKT

Other posttranslational modifications (PTMs) of FOXOs

The role of FOXOs to suppress tumorigenesis

Paradoxical role for FOXOs in controlling the fate of cancer

FOXOs regulate cell metabolism in multiple organs

The role of FOXOs in regulating beta cells

The mechanism underlying the role of FOXOs in regulating different cancers

Conflict of interest

Acknowledgements

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Cancer Cell

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Cell Metab.

Diabetes Metab.

Unified nomenclature for the winged helix/forkhead transcription factors

Genes Dev.

Update of human and mouse forkhead box (FOX) gene families

Hum. Genom.

Structure/function relationships underlying regulation of FOXO transcription factors

Oncogene

FOXO transcription factors at the interface between longevity and tumor suppression

Oncogene

Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation

Proc. Natl. Acad. Sci. U. S. A.

Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues

Biochem. J

Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion

EMBO J.

FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons

J. Cell Biol.

Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR

EMBO J.

14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4

Biochemistry

14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport

J. Cell Biol.

Expression of Drosophila FOXO regulates growth and can phenocopy starvation

BMC Dev. Biol.

daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans

Genetics

daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans

Science

daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans

Science

Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB

Am. J. Physiol. Endocrinol. Metab.

Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass