The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently altered in cancer. WWOX binds several proteins and thus is postulated to be involved in a variety of cellular processes. Interestingly, Wwox-knockout mice develop normally in utero but succumb to hypoglycemia and other metabolic defects early in life resulting in their death by 3–4 weeks of age. Cumulative evidence has linked WWOX with cellular metabolism including steroid metabolism, high-density lipoprotein cholesterol (HDL-C) metabolism, bone metabolism and, more recently, glucose metabolism. In this review, we discuss these evolving functions for WWOX and how its deletion affects cellular metabolism and neoplastic progression.
HanahanDWeinbergRA. The hallmarks of cancer. Cell2000; 100: 57–70.
2.
HanahanDWeinbergRA. Hallmarks of cancer: the next generation. Cell2011; 144: 646–74.
3.
BednarekAKKeck-WaggonerCLDanielRLLaflinKJBergsagelPLKiguchiKBrennerAJAldazCM. WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. Cancer Res2001; 61: 8068–73.
4.
SalahZAlianAAqeilanRI. WW domain-containing proteins: retrospectives and the future. Front Biosci2012; 17: 331–48.
5.
AqeilanRICroceCM. WWOX in biological control and tumorigenesis. J Cell Physiol2007; 212: 307–10.
6.
NunezMILudes-MeyersJAldazCM. WWOX protein expression in normal human tissues. J Mol Histol2006; 37: 115–25.
7.
GardenswartzAAqeilanRI. WW domain-containing oxidoreductase's role in myriad cancers: clinical significance and future implications. Exp Biol Med2014; 239: 253–63.
8.
PaigeAJTaylorKJTaylorCHillierSGFarringtonSScottDPorteousDJSmythJFGabraHWatsonJE. WWOX: a candidate tumor suppressor gene involved in multiple tumor types. Proc Natl Acad Sci U S A2001; 98: 11417–22.
9.
AqeilanRITrapassoFHussainSCostineanSMarshallDPekarskyYHaganJPZanesiNKaouMSteinGSLianJBCroceCM. Targeted deletion of Wwox reveals a tumor suppressor function. Proc Natl Acad Sci U S A2007; 104: 3949–54.
10.
AqeilanRIHassanMQde BruinAHaganJPVoliniaSPalumboTHussainSLeeSHGaurTSteinGSLianJBCroceCM. The WWOX tumor suppressor is essential for post-natal survival and normal bone metabolism. J Biol Chem2008; 283: 21629–39.
11.
SalahZAqeilanRHuebnerK. WWOX gene and gene product: tumor suppression through specific protein interactions. Future Oncol2010; 6: 249–59.
12.
Abu-OdehMBar-MagTHuangHKimTSalahZAbdeenSKSudolMReichmannDSidhuSKimPMAqeilanRI. Characterizing WW domain interactions of tumor suppressor WWOX reveals its association with multiprotein networks. J Biol Chem2014; 289: 8865–80.
AqeilanRIPalamarchukAWeigelRJHerreroJJPekarskyYCroceCM. Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2 gamma transcription factor. Cancer Res2004; 64: 8256–61.
15.
AqeilanRIPekarskyYHerreroJJPalamarchukALetofskyJDruckTTrapassoFHanSYMelinoGHuebnerKCroceCM. Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci U S A2004; 101: 4401–6.
16.
AbdeenSKDel MareSHussainSAbu-RemailehMSalahZHaganJRawahnehMPuXARussellSSteinJLSteinGSLianJBAqeilanRI. Conditional inactivation of the mouse Wwox tumor suppressor gene recapitulates the null phenotype. J Cell Physiol2013; 228: 1377–82.
17.
AqeilanRIHaganJPAqeilanHAPichiorriFFongLYCroceCM. Inactivation of the Wwox Gene accelerates fore stomach tumor progression in vivo. Cancer Res2007; 67: 5606–10.
18.
Ludes-MeyersJHKilHNunezMIContiCJParker-ThornburgJBedfordMTAldazCM. WWOX hypomorphic mice display a higher incidence of B-cell lymphomas and develop testicular atrophy. Genes Chromosomes Cancer2007; 46: 1129–36.
19.
Ludes-MeyersJHKilHParker-ThornburgJKusewittDFBedfordMTAldazCM. Generation and characterization of mice carrying a conditional allele of the Wwox tumor suppressor gene. PLoS One2009; 4: e7775–e7775.
20.
AqeilanRIHaganJPde BruinARawahnehMSalahZGaudioESiddiquiHVoliniaSAlderHLianJBSteinGSCroceCM. Targeted ablation of the WW domain-containing oxidoreductase tumor suppressor leads to impaired steroidogenesis. Endocrinology2009; 150: 1530–5.
21.
AbdeenSKSalahZKhawaledSAqeilanRI. Characterization of WWOX inactivation in murine mammary gland development. J Cell Physiol2013; 228: 1391–6.
22.
FergusonBWGaoXKilHLeeJBenavidesFAbbaMCAldazCM. Conditional Wwox deletion in mouse mammary gland by means of two Cre recombinase approaches. PLoS One2012; 7: e36618–e36618.
23.
AqeilanRIDonatiVGaudioENicolosoMSSundvallMKorhonenALundinJIsolaJSudolMJoensuuHCroceCMEleniusK. Association of Wwox with ErbB4 in breast cancer. Cancer Res2007; 67: 9330–6.
24.
NunezMILudes-MeyersJAbbaMCKilHAbbeyNWPageRESahinAKlein-SzantoAJAldazCM. Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status. Breast Cancer Res Treat2005; 89: 99–105.
25.
GulerGUnerAGulerNHanSYIliopoulosDHauckWWMcCuePHuebnerK. The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma. Cancer2004; 100: 1605–14.
26.
Saluda-GorgulASetaKNowakowskaMBednarekAK. WWOX oxidoreductase–substrate and enzymatic characterization. Z Naturforsch C2011; 66: 73–82.
27.
Del MareSKurekKCSteinGSLianJBAqeilanRI. Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma. Am J Cancer Res2011; 1: 585–94.
28.
KurekKCDel MareSSalahZAbdeenSSadiqHLeeSHGaudioEZanesiNJonesKBDeYoungBAmirGGebhardtMWarmanMSteinGSSteinJLLianJBAqeilanRI. Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression. Cancer Res2010; 70: 5577–86.
29.
YangJCogdellDYangDHuLLiHZhengHDuXPangYTrentJChenKZhangW. Deletion of the WWOX gene and frequent loss of its protein expression in human osteosarcoma. Cancer Lett2010; 291: 31–8.
30.
YangJZhaoLTianWLiaoZZhengHWangGChenK. Correlation of WWOX, RUNX2 and VEGFA protein expression in human osteosarcoma. BMC Med Genomics2013; 6: 56–56.
31.
MartinJWZielenskaMSteinGSvan WijnenAJSquireJA. The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma2011; 2011: 282745–282745.
32.
LeeJCWeissglas-VolkovDKyttalaMDastaniZCantorRMSobelEMPlaisierCLEngertJCvan GreevenbroekMMKaneJPMalloyMJPullingerCRHuertas-VazquezAAguilar-SalinasCATusie-LunaTde BruinTWAouizeratBEvan der KallenCCCroceCMAqeilanRIMarcilMViikariJSLehtimakiTRaitakariOTKuusistoJLaaksoMTaskinenMRGenestJPajukantaP. WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels. Am J Hum Genet2008; 83: 180–92.
33.
Iatan I, Choi HY, Ruel I, Reddy MV, Kil H, Lee J, Abu Odeh M, Salah Z, Abu-Remaileh M, Weissglas-Volkov D, Nikkola E, Civelek M, Awan Z, Croce CM, Aqeilan RI, Pajukanta P, Aldaz CM, Genest J. The WWOX gene modulates HDL and lipid metabolism. Circ Cardiovasc Genet 2014;7:491–504.
34.
SaezMEGonzalez-PerezAMartinez-LarradMTGayanJRealLMSerrano-RiosMRuizA. WWOX gene is associated with HDL cholesterol and triglyceride levels. BMC Med Genet2010; 11: 148–148.
35.
LeducMSLyonsMDarvishiKWalshKSheehanSAmendSCoxAOrho-MelanderMKathiresanSPaigenBKorstanjeR. The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol. J Lipid Res2011; 52: 1139–49.
LuntSYVander HeidenMG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol2011; 27: 441–64.
38.
WarburgO. On the origin of cancer cells. Science1956; 123: 309–14.
39.
O'KeefeLVColellaADayanSChenQChooAJacobRPriceGVenterDRichardsRI. Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species. Hum Mol Genet2011; 20: 497–509.
40.
DayanSO'KeefeLVChooARichardsRI. Common chromosomal fragile site FRA16D tumor suppressor WWOX gene expression and metabolic reprograming in cells. Genes Chromosomes Cancer2013; 52: 823–31.
41.
Abu-Remaileh M, Aqeilan RI. Tumor suppressor WWOX regulates glucose metabolism via HIF1alpha modulation. Cell Death Differ 2014;21:1805–14.
42.
DenkoNC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer2008; 8: 705–13.
43.
WeidemannAJohnsonRS. Biology of HIF-1alpha. Cell Death Differ2008; 15: 621–7.
44.
ChenQVazquezEJMoghaddasSHoppelCLLesnefskyEJ. Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem2003; 278: 36027–31.
45.
RiedKFinnisMHobsonLMangelsdorfMDayanSNancarrowJKWoollattEKremmidiotisGGardnerAVenterDBakerERichardsRI. Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells. Hum Mol Genet2000; 9: 1651–63.
46.
Del MareSSalahZAqeilanRI. WWOX: its genomics, partners, and functions. J Cell Biochem2009; 108: 737–45.
GourleyCPaigeAJTaylorKJWardCKuskeBZhangJSunMJanczarSHarrisonDJMuirMSmythJFGabraH. WWOX gene expression abolishes ovarian cancer tumorigenicity in vivo and decreases attachment to fibronectin via integrin alpha3. Cancer Res2009; 69: 4835–42.
