The increase in blood glucose concentrations seen in diabetes is associated with increased risk for cancer. Chocarro-Calvo et al. investigated the effect of high glucose concentrations on Wnt signaling, a pathway that can be activated in various human cancers. Under basal conditions, the Wnt effector β-catenin is phosphorylated by glycogen synthase kinase 3β (GSK-3β), which triggers its proteasomal degradation and prevents its translocation to the nucleus. Wnt3a or inhibition of GSK-3β by lithium chloride (LiCl) results in the accumulation of β-catenin in the nucleus, where it interacts with transcription factors in the TCF/LEF (T cell factor/lymphoid enhancer factor) family to transcriptionally activate target genes. Imaging analysis and Western blotting of subcellular fractions of neuroendocrine STC-1 cells indicated that although Wnt3a and LiCl increased the amount of cytoplasmic β-catenin, a high glucose concentration was also required to induce nuclear localization of β-catenin. A combination of LiCl and high glucose, but neither alone, induced the association of LEF-1 and β-catenin. Nuclear accumulation of β-catenin is enhanced by its acetylation, and combined LiCl and high glucose increased the acetylation of β-catenin as well as the abundance of the acetylase p300 and its association with LEF-1, whereas it decreased the activity of the deacetylase SIRT1. The p300 inhibitor C464 abrogated the glucose-induced nuclear accumulation and acetylation of β-catenin, whereas the activity of a TCF/LEF reporter gene was increased by the sirtuin inhibitor nicotinamide (NAA) and decreased by the sirtuin enhancer resveratrol. A K354R β-catenin mutant showed reduced acetylation and did not accumulate in the nucleus in response to combined LiCl and high glucose. In addition, combined LiCl and high glucose enhanced the binding of LEF-1 and β-catenin to various target promoters in STC-1 cells and the nuclear accumulation of β-catenin in various human cancer cell lines. Thus, high glucose concentrations stimulate Wnt signaling by promoting the acetylation and nuclear accumulation of β-catenin.
A. Chocarro-Calvo, J. M. García-Martínez, S. Ardila-González, A. De la Vieja, C. García-Jiménez, Glucose-induced β-catenin acetylation enhances Wnt signaling in cancer. Mol. Cell 49, 474-486 (2013). [Online Journal]