title: Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species.
abstract: Common chromosomal fragile sites FRA3B and FRA16D are frequent sites of DNA instability in cancer, but their contribution to cancer cell biology is not yet understood. Genes that span these sites (FHIT and WWOX, respectively) are often perturbed (either increased or decreased) in cancer cells and both are able to suppress tumour growth. While WWOX has some tumour suppressor characteristics, its normal role and functional contribution to cancer has not been fully determined. We find that a significant proportion of Drosophila Wwox interactors identified by proteomics and microarray analyses have roles in aerobic metabolism. Functional relationships between Wwox and either CG6439/isocitrate dehydrogenase (Idh) or Cu-Zn superoxide dismutase (Sod) were confirmed by genetic interactions. In addition, altered levels of Wwox resulted in altered levels of endogenous reactive oxygen species. Wwox (like FHIT) contributes to pathways involving aerobic metabolism and oxidative stress, providing an explanation for the 'non-classical tumour suppressor' behaviour of WWOX. Fragile sites, and the genes that span them, are therefore part of a protective response mechanism to oxidative stress and likely contributors to the differences seen in aerobic glycolysis (Warburg effect) in cancer cells.
authors.affiliation: ARC Special Research Centre for the Molecular Genetics of Development and Discipline of Genetics, School ofMolecular and Biomedical Sciences, The University of Adelaide, Adelaide S.A. 5005, Australia.
authors.forename: Louise V
authors.initials: LV
authors.lastname: O'Keefe
authors.forename: Alex
authors.initials: A
authors.lastname: Colella
authors.forename: Sonia
authors.initials: S
authors.lastname: Dayan
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Chen
authors.forename: Amanda
authors.initials: A
authors.lastname: Choo
authors.forename: Reuben
authors.initials: R
authors.lastname: Jacob
authors.forename: Gareth
authors.initials: G
authors.lastname: Price
authors.forename: Deon
authors.initials: D
authors.lastname: Venter
authors.forename: Robert I
authors.initials: RI
authors.lastname: Richards
mesh_terms: D000332:Aerobiosis; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D019069:Cell Respiration; D043283:Chromosome Fragile Sites; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006019:Glycolysis; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D046228:Microarray Analysis; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C559480:WWOX protein, Drosophila; C486071:WWOX protein, human; D007521:Isocitrate Dehydrogenase; D013482:Superoxide Dismutase