cancer 2-Garcia-Jimenez

Glucose-induced β-catenin acetylation enhances Wnt signaling in cancer.

Mol Cell. 2013 Feb 7;49(3):474-86.

Chocarro-Calvo A, García-Martínez JM, Ardila-González S, De la Vieja A, García-Jiménez C.

Departamento de Fisiología y Bioquímica, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Madrid, Spain.

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.

PMID: 23273980

Importance:

It has a high impact in health, since diabetes and obesity are pandemic and this explains the molecular basis for higher cancer risk in the diabetic population. It may inform political decissions concerning health, guide new epidemiological studies and open new therapeutic strategies. In addition it reveals that the “dogma” of Wnt signalling sending β-catenin to the nucleus to increase expression of proliferation genes does not stand on its own, high glucose is required and increased glucose uptake by tumors may ensure that.

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