title: The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of β-catenin and cell proliferation.
abstract: The short half-life protooncogene β-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 β-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 β-catenin and O-GlcNAcylation levels in the colon. MCF7 cells possessing intact Wnt/β-catenin signaling heavily expressed β-catenin when cultured in high glucose; this was reversed by the HBP inhibitor azaserine. HBP inhibition also decreased the expression of β-catenin in HT29 and, to a lesser extent, HCT116 cells. The same observation was made with regard to the transcriptional activity of β-catenin in HEK293 cells. Inhibition of HBP also blocked the glucose-mediated proliferation capacity of MCF7 cells, demonstrating that glucose affects both β-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 β-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 β-catenin.
authors: CNRS-UMR 8576, Unit of Structural and Functional Glycobiology, University of Lille 1, Villeneuve d'Ascq, France.
authors: Stéphanie
authors: S
authors: Olivier-Van Stichelen
authors: Céline
authors: C
authors: Guinez
authors: Anne-Marie
authors: AM
authors: Mir
authors: Yobana
authors: Y
authors: Perez-Cervera
authors: Chunming
authors: C
authors: Liu
authors: Jean-Claude
authors: JC
authors: Michalski
authors: Tony
authors: T
authors: Lefebvre
mesh_terms: D000215:Acylation; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001377:Azaserine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D005215:Fasting / Q000378:metabolism; D005944:Glucosamine / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011499:Protein Processing, Post-Translational; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: D000964:Antimetabolites, Antineoplastic; D051176:beta Catenin; D001377:Azaserine; D005947:Glucose; D005944:Glucosamine