title: Glucose-induced β-catenin acetylation enhances Wnt signaling in cancer.
abstract: Nuclear accumulation of β-catenin, a widely recognized marker of poor cancer prognosis, drives cancer cell proliferation and senescence bypass and regulates incretins, critical regulators of fat and glucose metabolism. Diabetes, characterized by elevated blood glucose levels, is associated with increased cancer risk, partly because of increased insulin growth factor 1 signaling, but whether elevated glucose directly impacts cancer-associated signal-transduction pathways is unknown. Here, we show that high glucose is essential for nuclear localization of β-catenin in response to Wnt signaling. Glucose-dependent β-catenin nuclear retention requires lysine 354 and is mediated by alteration of the balance between p300 and sirtuins that trigger β-catenin acetylation. Consequently β-catenin accumulates in the nucleus and activates target promoters under combined glucose and Wnt stimulation, but not with either stimulus alone. Our results reveal a mechanism by which high glucose enhances signaling through the cancer-associated Wnt/β-catenin pathway and may explain the increased frequency of cancer associated with obesity and diabetes.
authors.affiliation: Departamento de Fisiología y Bioquímica, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Chocarro-Calvo
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: García-Martínez
authors.forename: Soraya
authors.initials: S
authors.lastname: Ardila-González
authors.forename: Antonio
authors.initials: A
authors.lastname: De la Vieja
authors.forename: Custodia
authors.initials: C
authors.lastname: García-Jiménez
mesh_terms: D000107:Acetylation / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D037761:Sirtuins / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002843:Chromatin; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051820:TCF Transcription Factors; D060509:Wnt3A Protein; D051176:beta Catenin; D005749:Gastric Inhibitory Polypeptide; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D037761:Sirtuins; D018021:Lithium Chloride; D005947:Glucose