FoxO transcription factors in cancer metabolism

doi:10.1016/j.semcancer.2018.01.004

Seminars in Cancer Biology

Volume 50, June 2018, Pages 65-76

https://doi.org/10.1016/j.semcancer.2018.01.004 Get rights and content

Abstract

FoxO transcription factors serve as the central regulator of cellular homeostasis and are tumor suppressors in human cancers. Recent studies have revealed that, besides their classic functions in promoting cell death and inducing cell cycle arrest, FoxOs also regulate cancer metabolism, an emerging hallmark of cancer. In this review, we summarize the regulatory mechanisms employed to control FoxO activities in the context of cancer biology, and discuss FoxO function in metabolism reprogramming in cancer and interaction with other key cancer metabolism pathways. A deeper understanding of FoxOs in cancer metabolism may reveal novel therapeutic opportunities in cancer treatment.

Introduction

In order to maintain cellular homeostasis, metazoans have evolved an intricate signaling network which senses and adapts to the changes in the extracellular or intracellular environment. Successful adaptation and long-term survival under altered physiological conditions are dependent on the precise regulation of gene expression, which is mainly controlled by the specific recruitment of transcription factors (TFs) to the target gene promoters or enhancer regions. Therefore, TFs serve as the ultimate effector molecules and even define the fate of a cell [1]. The human genome encodes around 2000 TFs, which regulate a diverse array of cellular processes ranging from cell division to cell death [2]. Dysregulation of TFs results in various pathological conditions including cancer. Indeed, TFs have often been found to be mutated, deleted, or amplified in many cancers, and therefore have been considered as attractive therapeutic targets for cancer treatment [3].

The forkhead box O (FoxO) family of TFs are the central regulator to the metazoan physiology and have diverse cellular functions including cell cycle, cell growth, apoptosis, autophagy, stress resistance, protection from aggregate toxicity, DNA repair, tumor suppression, and metabolism [[4], [5], [6], [7], [8]]. They have also been implicated in the regulation of organ development, stem cell maintenance, and cell differentiation, suggesting their crucial roles in development [[9], [10], [11]]. FoxOs belong to the superfamily of TFs known as forkhead box TFs and are characterized by the presence of an evolutionarily conserved winged-helix DNA binding motif and the forkhead domain [8]. The expression of FoxO target genes is regulated by selective recruitment of FoxOs to the consensus DNA sequence TTGTTAC and their interactions with other TFs [8]. FoxOs are evolutionarily conserved and have a single orthologue in invertebrates, such as DAF-16 in Caenorhabditis elegans and dFOXO in Drosophila melanogaster. In contrast, mammalian FoxOs consist of at least four members: FoxO1, FoxO3, FoxO4, and FoxO6. The expression of specific FoxO members in mammals varies among different tissues and is regulated in a spatiotemporal manner during various developmental stages [12,13]. In addition, FoxO TFs sense the changes in the extracellular or intracellular environment and their activities are also regulated by different types of signaling stimuli, including growth factors that activate the phosphatidyl-inositol-3-kinases (PI3K)-AKT (also known as PKB) pathway and different stress signaling, such as oxidative stress [6]. Tight regulation of FoxO transcriptional activity by complex signaling networks ensures that specific gene expression switch coordinates with environmental cues. FoxOs have been implicated in various diseases, including cancer. FoxOs generally exert tumor suppression functions by promoting cell cycle arrest, apoptosis, stress resistance, and DNA repair in cancer cells, and are inactivated in various human cancers [4,14]. In addition, FoxOs act as a central regulator of cellular metabolism and longevity [5,15], thereby placing FoxOs at the crossroad of cancer and metabolism.

In this review, we first present a detailed discussion on the intricate regulatory mechanisms employed to fine-tune the transcriptional activities of FoxOs in cancer, followed by a discussion of the biological roles of FoxOs in tumor suppression. We then focus on the new insights in FoxO regulation of cancer metabolism. Finally, we discuss the cross talks between FoxOs and other important pathways/cellular processes involved in cancer metabolism. It is important to note that FoxO regulation of metabolism also plays pivotal roles in insulin resistance, diabetes, and obesity [7,16,17]. However, this topic will be beyond the scope of this review focusing on metabolic function of FoxOs in cancer.

Section snippets

Molecular mechanisms of FoxO regulation

FoxO TFs are regulated by the coordinated actions of multiple signaling pathways at several mechanistic levels, including regulation of FoxO transcriptional activity, cellular localization, protein stability, and mRNA levels (Fig. 1). These multiple modes of regulation ensure the condition-specific activation or inhibition of FoxOs. Notably, many of the FoxO regulators also play instrumental roles in cancer biology, and the regulatory modes to control FoxOs are often dysregulated in cancer.

FoxOs in cancers

The relevance of FoxOs to human cancers was initially realized when FoxOs were identified as fusion products that resulted from chromosomal translocation in different cancers, including FoxO1 in alveolar rhabdomyosarcomas, and FoxO3 and FoxO4 in AML [[96], [97], [98]]. Since then, FoxOs have been implicated in the pathogenesis of various cancers. FoxO generally function as tumor suppressors in cancers, and the tumor suppressive roles of FoxOs are supported by three major lines of evidence.

Roles of FoxOs in cancer metabolism

Metabolic rewiring in cancer cells has been recognized as a new hallmark of cancer in recent years [132]. In order to support their increased biosynthetic and bioenergetic needs, to maintain the redox balance, and to survive under metabolic stress conditions resulting from tumor growth and poor vasculature within tumor mass, cancer cells extensively remodel their metabolic networks, partly through reprogramming gene transcription [133]. For example, many cancer cells upregulate the expression

FoxO crosstalk with other major cancer metabolism pathways

Altered cellular metabolism now is widely recognized as a hallmark of cancer [132]. However, except a few notable examples (such as IDH1 mutations in gliomas and AML [159]), metabolic enzymes are generally not mutated in human cancers. Instead, deregulated cellular metabolism in cancer is mainly driven by cancer signaling pathways that reprogram metabolism networks in cancer cells, prominent among which are the PI3K-AKT pathway, the LKB1-AMPK pathway, mTOR, and several transcription factors

Conclusion and perspectives

Emerging evidence supports the critical roles of FoxO TFs in the regulation of cancer metabolism. FoxOs are regulated by a diverse array of signaling networks that sense nutrient status and mediate stress response in the cells, and these intricate regulatory modes to control FoxO activity are significantly altered in human cancers. FoxOs repress tumor metabolism by inhibiting glycolysis and other metabolism processes for biosynthesis as well as by modulating other key cancer metabolism

Conflict of interest

The authors have no conflict of interest to declare.

Acknowledgements

We apologize to the many collogues whose related work cannot be cited due to space limitations. We are grateful for funding support from the Andrew Sabin Family Fellow Award and Institutional Research Grant from the University of Texas MD Anderson Cancer Center, National Institutes of Health (CA181196 and CA190370), Anna Fuller Fund, and Ellison Medical Foundation (AG-NS-0973-13). B. G. is an Ellison Medical Foundation New Scholar and an Andrew Sabin Family Fellow.

References (183)

T.I. Lee et al.
Transcriptional regulation and its misregulation in disease
Cell
(2013)
A.S. Bhagwat et al.
Targeting transcription factors in cancer
Trends Cancer
(2015)
Z. Tothova et al.
FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
Cell
(2007)
M.F. Hoekman et al.
Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain
Gene Expr. Patterns
(2006)
D. Accili et al.
FoxOs at the crossroads of cellular metabolism, differentiation, and transformation
Cell
(2004)
D.A. Fruman et al.
The PI3K pathway in human disease
Cell
(2017)
T. Maehama et al.
The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
J. Biol. Chem.
(1998)
A. Brunet et al.
Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor
Cell
(1999)
G. Rena et al.
Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B
J. Biol. Chem.
(1999)
E.D. Tang et al.
Negative regulation of the forkhead transcription factor FKHR by Akt
J. Biol. Chem.
(1999)

G. Tzivion et al.

FoxO transcription factors; Regulation by AKT and 14-3-3 proteins

Biochim. Biophys. Acta

(2011)

F.M. Jacobs et al.

FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics

J. Biol. Chem.

(2003)

M.C. Wang et al.

JNK. extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling

Cell

(2005)

M.K. Lehtinen et al.

A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span

Cell

(2006)

W. Bi et al.

N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82

J. Biol. Chem.

(2010)

E.L. Greer et al.

The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor

J. Biol. Chem.

(2007)

E.L. Greer et al.

An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans

Curr. Biol.

(2007)

H. Yadav et al.

TGF-beta1/Smad3 pathway targets PP2A-AMPK-FoxO1 signaling to regulate hepatic gluconeogenesis

J. Biol. Chem.

(2017)

K.K. Ho et al.

Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin

J. Biol. Chem.

(2012)

T.R. Kress et al.

The MK5/PRAK kinase and Myc form a negative feedback loop that is disrupted during colorectal tumorigenesis

Mol. Cell

(2011)

S. Yalcin et al.

Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells

J. Biol. Chem.

(2008)

M.C. Hu et al.

IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a

Cell

(2004)

N. Chapuis et al.

IkappaB kinase overcomes PI3K/Akt and ERK/MAPK to control FOXO3a activity in acute myeloid leukemia

Blood

(2010)

D.R. Plas et al.

Akt activation promotes degradation of tuberin and FOXO3a via the proteasome

J. Biol. Chem.

(2003)

W. Fu et al.

MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation

J. Biol. Chem.

(2009)

F. Li et al.

C terminus of Hsc70-interacting protein promotes smooth muscle cell proliferation and survival through ubiquitin-mediated degradation of FoxO1

J. Biol. Chem.

(2009)

S. Kato et al.

COP1 functions as a FoxO1 ubiquitin E3 ligase to regulate FoxO1-mediated gene expression

J. Biol. Chem.

(2008)

A. Drazic et al.

The world of protein acetylation

Biochim. Biophys. Acta

(2016)

L. Qiang et al.

Uncoupling of acetylation from phosphorylation regulates FoxO1 function independent of its subcellular localization

J. Biol. Chem.

(2010)

A. van der Horst et al.

FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1)

J. Biol. Chem.

(2004)

A.H. Tseng et al.

SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage

Free Radic. Biol. Med.

(2013)

K. Yamagata et al.

Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt

Mol. Cell

(2008)

M. Kuo et al.

O-glycosylation of FoxO1 increases its transcriptional activity towards the glucose 6-phosphatase gene

FEBS Lett.

(2008)

M.P. Housley et al.

O-GlcNAc regulates FoxO activation in response to glucose

J. Biol. Chem.

(2008)

K. Nowak et al.

E2F-1 regulates expression of FOXO1 and FOXO3a

Biochim. Biophys. Acta

(2007)

E. Angelis et al.

The role of E2F-1 and downstream target genes in mediating ischemia/reperfusion injury in vivo

J. Mol. Cell. Cardiol.

(2011)

W.J. Bakker et al.

FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2

Mol. Cell

(2007)

A. Essaghir et al.

The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors

J. Biol. Chem.

(2009)

J. Hillion et al.

AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily

Blood

(1997)

J.H. Paik et al.

FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis

Cell

(2007)

M. Iwafuchi-Doi et al.

Cell fate control by pioneer transcription factors

Development

(2016)

Y. Zhang et al.

FoxO family members in cancer

Cancer Biol. Ther.

(2011)

A. van der Horst et al.

Stressing the role of FoxO proteins in lifespan and disease

Nat. Rev. Mol. Cell Biol.

(2007)

A. Eijkelenboom et al.

FOXOs: signalling integrators for homeostasis maintenance

Nat. Rev. Mol. Cell Biol.

(2013)

K. Maiese

FoxO transcription factors and regenerative pathways in diabetes mellitus

Curr. Neurovasc. Res.

(2015)

D.R. Calnan et al.

The FoxO code

Oncogene

(2008)

S.M. Bartell et al.

FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation

Nat. Commun.

(2014)

S.M. Hedrick et al.

FOXO transcription factors throughout T cell biology

Nat. Rev. Immunol.

(2012)

T. Furuyama et al.

Effects of aging and caloric restriction on the gene expression of Foxo1, 3, and 4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles

Microsc. Res. Tech.

(2002)

E.L. Greer et al.

FOXO transcription factors at the interface between longevity and tumor suppression

Oncogene

(2005)

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¹: These authors contributed equally to this work.

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ReviewFoxO transcription factors in cancer metabolism

Abstract

Introduction

Section snippets

Molecular mechanisms of FoxO regulation

FoxOs in cancers

Roles of FoxOs in cancer metabolism

FoxO crosstalk with other major cancer metabolism pathways

Conclusion and perspectives

Conflict of interest

Acknowledgements

Cell

Trends Cancer

Cell

Gene Expr. Patterns

Cell

Cell

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Curr. Biol.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

Cell

Blood

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Free Radic. Biol. Med.

Mol. Cell

FEBS Lett.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Mol. Cell. Cardiol.

Mol. Cell

J. Biol. Chem.

Blood

Cell

Cell fate control by pioneer transcription factors

Development

FoxO family members in cancer

Cancer Biol. Ther.

Stressing the role of FoxO proteins in lifespan and disease

Nat. Rev. Mol. Cell Biol.

FOXOs: signalling integrators for homeostasis maintenance

Nat. Rev. Mol. Cell Biol.

FoxO transcription factors and regenerative pathways in diabetes mellitus

Curr. Neurovasc. Res.

The FoxO code

Oncogene

FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation

Nat. Commun.

FOXO transcription factors throughout T cell biology

Nat. Rev. Immunol.

Effects of aging and caloric restriction on the gene expression of Foxo1, 3, and 4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles

Microsc. Res. Tech.

FOXO transcription factors at the interface between longevity and tumor suppression

Oncogene

Review
FoxO transcription factors in cancer metabolism