Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation

Abu-Remaileh, Muhannad; Aqeilan, Rami I.

doi:10.1038/cdd.2014.95

Cited by 73 publications

(124 citation statements)

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“…In fact, Rasmediated transformation of Wwox-KO MEFs results in an increased number of tumorigenic cells compared with WT cells, suggesting that WWOX deficiency facilitates transformation (60). Deletion or attenuation of WWOX is observed in early preneoplastic breast lesions (61,62) and targeted ablation of murine Wwox-associated mammary tumor formation (16).…”

Section: Discussionmentioning

confidence: 99%

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Abu-Odeh

Salah

Herbel

et al. 2014

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

122

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Genomic instability is a hallmark of cancer. The WW domaincontaining oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.genomic instability | common fragile sites | WW domain-containing oxidoreductase | ataxia telangiectasia-mutated | ITCH G enomic instability is a common characteristic of human cancers. The DNA damage response (DDR) maintains the integrity of the genome in response to DNA damage. DDR is a complex signaling process that results in cell cycle arrest followed by either DNA repair or apoptosis if the DNA damage is too extensive to be repaired (1-3). Key mammalian damage response sensors are ataxia telangiectasia-mutated (ATM), ATM and Rad3-related, and DNA-dependent PKs (4, 5). Disruption of the DDR machinery in human cells leads to genomic instability and an increased risk of cancer progression (6, 7).The WW domain-containing oxidoreductase (WWOX) gene spans the common fragile site (CFS) FRA16D (8, 9). Genomic alterations affecting the WWOX locus have been reported in several types of cancer and include homozygous and hemizygous deletions (10-13). Ectopic expression of WWOX in WWOXnegative cancer cells attenuates cell growth and suppresses tumor growth in immunocompromised mice (10,11,14). Importantly, targeted ablation of Wwox in mice results in higher incidence of spontaneous lesions resembling osteosarcomas and lung and mammary tumors (14-16). These findings suggest WWOX as a tumor suppressor. The WWOX protein contains two Nterminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11, 17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3). The mechanism by which WWOX suppresses tumorigenicity is, however, not well-known.In vitro, CFSs are defined as gaps or breaks on metaphase chromosomes that occur in cells treated with inhibitors of DNA replication (19,20). In vivo, CFSs are preferential targets of replication stress in preneoplastic lesions (21), and emerging evidence suggests that they represent early warning sensors for DNA damage (22-24). ...

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Section: Discussionmentioning

confidence: 99%

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Abu-Odeh

Salah

Herbel

et al. 2014

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

122

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“…54 HIF-1a upregulation induced by loss of WWOX expression is associated with tumorigenesis in mice. 54 How WWOX controls HIF-1a expression is unclear. WWOX deficiency decreases mitochondrial respiration in mouse embryonic fibroblasts.…”

Section: Wwox Functions As a Tumor Suppressormentioning

confidence: 99%

“…54 Warburg effect is a hallmark of cancer cells manifested by high rates of aerobic glycolysis and high levels of lactate and pyruvate generation. WWOX physically interacts with hypoxia-inducible transcription factor 1a (HIF-1a) and suppresses HIF-1a-mediated transcriptional activation of downstream targets such as glucose transporter 1 (GLUT1) (Figure 2).…”

Section: Wwox Functions As a Tumor Suppressormentioning

confidence: 99%

“…WWOX physically interacts with hypoxia-inducible transcription factor 1a (HIF-1a) and suppresses HIF-1a-mediated transcriptional activation of downstream targets such as glucose transporter 1 (GLUT1) (Figure 2). 54 The reduced expression of GLUT1 leads to the downregulation of glucose uptake and glycolysis in cells. 54 HIF-1a upregulation induced by loss of WWOX expression is associated with tumorigenesis in mice.…”

Section: Wwox Functions As a Tumor Suppressormentioning

confidence: 99%

“…54 The reduced expression of GLUT1 leads to the downregulation of glucose uptake and glycolysis in cells. 54 HIF-1a upregulation induced by loss of WWOX expression is associated with tumorigenesis in mice. 54 How WWOX controls HIF-1a expression is unclear.…”

Section: Wwox Functions As a Tumor Suppressormentioning

confidence: 99%

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Regulation of cell signaling and apoptosis by tumor suppressor WWOX

Chou

Lai

et al. 2015

Exp Biol Med (Maywood)

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Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell death induced by a variety of stress stimuli, such as tumor necrosis factor, UV radiation, and chemotherapeutic drug treatment. Loss of WWOX gene expression due to gene deletions, loss of heterozygosity, chromosomal translocations, or epigenetic silencing is frequently observed in human malignant cancer cells. Acquisition of chemoresistance in squamous cell carcinoma, osteosarcoma, and breast cancer cells is associated with WWOX deficiency. WWOX protein physically interacts with many signaling molecules and exerts its regulatory effects on gene transcription and protein stability and subcellular localization to control cell survival, proliferation, differentiation, autophagy, and metabolism. In this review, we provide an overview of the recent advances in understanding the molecular mechanisms by which WWOX regulates cellular functions and stress responses. A potential scenario is that activation of WWOX by anticancer drugs is needed to overcome chemoresistance and trigger cancer cell death, suggesting that WWOX can be regarded as a prognostic marker and a candidate molecule for targeted cancer therapies.

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Tumor suppressor WWOX moderates the mitochondrial respiratory complex

Choo

O’Keefe

Lee

et al. 2015

Genes Chromosomes & Cancer

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Fragile site FRA16D exhibits DNA instability in cancer, resulting in diminished levels of protein from the WWOX gene that spans it. WWOX suppresses tumor growth by an undefined mechanism. WWOX participates in pathways involving aerobic metabolism and reactive oxygen species. WWOX comprises two WW domains as well as a short-chain dehydrogenase/reductase enzyme. Herein is described an in vivo genetic analysis in Drosophila melanogaster to identify functional interactions between WWOX and metabolic pathways. Altered WWOX levels modulate variable cellular outgrowths caused by genetic deficiencies of components of the mitochondrial respiratory complexes. This modulation requires the enzyme active site of WWOX, and the defective respiratory complex-induced cellular outgrowths are mediated by reactive oxygen species, dependent upon the Akt pathway and sensitive to levels of autophagy and hypoxia-inducible factor. WWOX is known to contribute to homeostasis by regulating the balance between oxidative phosphorylation and glycolysis. Reduction of WWOX levels results in diminished ability to respond to metabolic perturbation of normal cell growth. Thus, the ability of WWOX to facilitate escape from mitochondrial damage-induced glycolysis (Warburg effect) is, therefore, a plausible mechanism for its tumor suppressor activity.

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Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation

Cited by 73 publications

References 48 publications

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response

Regulation of cell signaling and apoptosis by tumor suppressor WWOX

Tumor suppressor WWOX moderates the mitochondrial respiratory complex

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