FOXO family in regulating cancer and metabolism
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
Other posttranslational modifications (PTMs) of FOXOs
Besides phosphorylation of FOXOs by various kinases to regulate their functions, FOXOs are also subject to other PTMs in various physiological or pathological conditions. These PTMs include ubiquitination, acetylation, and methylation [44], and play a crucial role in regulating FOXOs’ activity and stability.
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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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.