Abstract
The post-translational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is regulated by a unique couple of enzymes. O-GlcNAc transferase (OGT) transfers the GlcNAc residue from UDP-GlcNAc, the final product of the hexosamine biosynthetic pathway (HBP), whereas O-GlcNAcase (OGA) removes it. This study and others show that OGT and O-GlcNAcylation levels are increased in cancer cell lines. In that context, we studied the effect of OGT silencing in the colon cancer cell lines HT29 and HCT116 and the primary colon cell line CCD841CoN. Herein, we report that OGT silencing diminished proliferation, in vitro cell survival and adhesion of primary and cancer cell lines. SiOGT dramatically decreased HT29 and CCD841CoN migration, CCD841CoN harboring high capabilities of migration in Boyden chamber system when compared to HT29 and HCT116. The expression levels of actin and tubulin were unaffected by OGT knockdown but siOGT seemed to disorganize microfilament, microtubule, and vinculin networks in CCD841CoN. While cancer cell lines harbor higher levels of OGT and O-GlcNAcylation to fulfill their proliferative and migratory properties, in agreement with their higher consumption of HBP main substrates glucose and glutamine, our data demonstrate that OGT expression is not only necessary for the biological properties of cancer cell lines but also for normal cells.
Highlights
O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is the modification by a single residue of N-acetylglucosamine (GlcNAc) of nucleocytoplasmic and mitochondrial proteins
Two colon cancer cell lines, HT29 and HCT116, respectively, derived from an adenocarcinoma and from a carcinoma (Table 1) and the fetal colon cell line CCD841CoN were analyzed by Western blot to determine to the levels of O-GlcNAcylation, O-GlcNAc transferase (OGT), OGA, and Glutamine:Fructose-6-P amidotransferase (GFAT), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP) (Figures 1A,B)
A deregulation in the O-GlcNAcylation cycling is involved in the etiology of diverse pathologies, such as type-2 diabetes, Alzheimer’s, and cancers [6]
Summary
O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is the modification by a single residue of N-acetylglucosamine (GlcNAc) of nucleocytoplasmic and mitochondrial proteins. This modification is highly dynamic and is regulated by two enzymes: the O-GlcNAc transferase (OGT), which adds the residue and the O-GlcNAcase (OGA), which removes it (Figure 1A). Deregulation of O-GlcNAcylation dynamics actively participates in tumorigenesis and in the etiology of cancer [5]. Glucose transport and consumption is upregulated in cancer cells. This alteration of metabolism is called the “Warburg effect,” Otto Warburg having devoted a large part of his research activities to “the origin of cancer cells” [9]
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