Medical College of Wisconsin
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The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of I?-catenin and cell proliferation. Am J Physiol Endocrinol Metab 2012 Feb 15;302(4):E417-24



Pubmed ID




Scopus ID

2-s2.0-84863017903   50 Citations


The short half-life protooncogene I?-catenin acquires a remarkable stability in a large subset of cancers, mainly from mutations affecting its proteasomal degradation. In this sense, colorectal cancers (CRC) form a group of pathologies in which early steps of development are characterized by an aberrant expression of I?-catenin and an uncontrolled proliferation of epithelial cells. Diet has long been described as an influence in the emergence of CRC, but the molecular events that link metabolic disorders and CRC remain elusive. Part of the explanation may reside in hexosamine biosynthetic pathway (HBP) flux. We found that fasted mice being force-fed with glucose or glucosamine leads to an increase of I?-catenin and O-GlcNAcylation levels in the colon. MCF7 cells possessing intact Wnt/I?-catenin signaling heavily expressed I?-catenin when cultured in high glucose; this was reversed by the HBP inhibitor azaserine. HBP inhibition also decreased the expression of I?-catenin in HT29 and, to a lesser extent, HCT116 cells. The same observation was made with regard to the transcriptional activity of I?-catenin in HEK293 cells. Inhibition of HBP also blocked the glucose-mediated proliferation capacity of MCF7 cells, demonstrating that glucose affects both I?-catenin expression and cell proliferation through the HBP. The ultimate element conducting these events is the dynamic posttranslational modification O-GlcNAcylation, which is intimately linked to HBP; the modulation of its level affected the expression of I?-catenin and cell proliferation. In accordance with our findings, we propose that metabolic disorders correlate to CRC via an upregulation of HBP that reverberates on high O-GlcNAcylation levels including modification of I?-catenin.

Author List

Olivier-Van Stichelen S, Guinez C, Mir AM, Perez-Cervera Y, Liu C, Michalski JC, Lefebvre T


Stephanie Olivier-Van Stichelen PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antimetabolites, Antineoplastic
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms
Mice, Inbred C57BL
Protein Processing, Post-Translational
Wnt Signaling Pathway
beta Catenin