Abstract
Changes in N-glycosylation of plasma proteins are observed in many types of cancer, nevertheless, few studies suggest the exact mechanism involved in aberrant protein glycosylation. Here we studied the impact of DNA methylation on the N-glycome in the secretome of the HepG2 cell line derived from hepatocellular carcinoma (HCC). Since the majority of plasma glycoproteins originate from the liver, the HepG2 cells represent a good model for glycosylation changes in HCC that are detectable in blood, which is an easily accessible analytic material in a clinical setting. Two different concentrations of 5-aza-2′-deoxycytidine (5-aza-2dC) differentially affected global genome methylation and induced different glycan changes. Around twenty percent of 84 glyco-genes analysed changed expression level after the 5-aza-2dC treatment as a result of global genome hypomethylation. A correlation study between the changes in glyco-gene expression and the HepG2 glycosylation profile suggests that the MGAT3 gene might be responsible for the glycan changes consistently induced by both doses of 5-aza-2dC. Core-fucosylated tetra-antennary structures were decreased in quantity likely as a result of hypomethylated MGAT3 gene promoter followed by increased expression of this gene.
Highlights
Glycosylation is an important post-translational modification that can significantly contribute to variability in protein structures[1,2]
Since majority of plasma proteins are produced by hepatocytes, and blood is the most convenient sample to search for diagnostic and prognostic markers in many diseases, we studied the impact of genome DNA hypomethylation on protein glycosylation in the hepatocellular carcinoma (HCC) cell line, HepG2
We propose that aberrant expression of the MGAT3 gene as a result of DNA hypomethylation is the mechanisms leading to the aberrant glyco-phenotype characteristic of HCC
Summary
Glycosylation is an important post-translational modification that can significantly contribute to variability in protein structures[1,2]. Is known about mechanisms leading to extensive changes in the plasma glycome composition in disease. Protein glycosylation is under strong genetic regulation when homeostasis is disturbed, for example during acute systemic inflammation, composition of both total plasma and IgG glycomes can change rapidly[9,17,18]. Since majority of plasma proteins are produced by hepatocytes, and blood is the most convenient sample to search for diagnostic and prognostic markers in many diseases, we studied the impact of genome DNA hypomethylation on protein glycosylation in the hepatocellular carcinoma (HCC) cell line, HepG2. We propose that aberrant expression of the MGAT3 gene as a result of DNA hypomethylation is the mechanisms leading to the aberrant glyco-phenotype characteristic of HCC
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