title: Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation.
abstract: The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1α (HIF1α) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1α and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1α levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the 'Warburg effect'. Furthermore, Wwox-deficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Abu-Remaileh
authors.affiliation: 1] The Lautenberg Center for General and Tumor Immunology, Department of Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel [2] Department of Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: R I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C428130:Wwox protein, mouse; D005947:Glucose