Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer

Sci Rep. 2016 Mar 23:6:23642. doi: 10.1038/srep23642.

Abstract

The molecular basis of aberrant protein glycosylation, a pathological alteration widespread in colorectal cancers (CRC), and the mechanisms by which it contributes to tumor progression remain largely unknown. We performed targeted re-sequencing of 430 glycosylation-associated genes in a series of patient-derived CRC cell lines (N = 31) and matched primary tumor tissues, identifying 12 new significantly mutated glycosylation-associated genes in colon cancer. In particular, we observed an enrichment of mutations in genes (B3GNT2, B4GALT2, ST6GALNAC2) involved in the biosynthesis of N- and Cores 1-3 O-linked glycans in the colon, accounting for ~16% of the CRCs tested. Analysis of independent large-scale tumor tissue datasets confirmed recurrent mutations within these genes in colon and other gastrointestinal cancers. Systematic biochemical and phenotypic characterization of the candidate wild-type and mutant glycosyltransferases demonstrated these mutations as either markedly altering protein localization, post-translational modification, encoded enzymatic activities and/or the migratory potential of colon carcinoma cells. These findings suggest that functionally deleterious mutations in glycosyltransferase genes in part underlie aberrant glycosylation, and contribute to the pathogenesis of molecular subsets of colon and other gastrointestinal malignancies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Colonic Neoplasms / genetics*
  • DNA Mutational Analysis / methods*
  • Galactosyltransferases / genetics*
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Glycosylation
  • Glycosyltransferases / genetics*
  • Humans
  • N-Acetylglucosaminyltransferases / genetics*
  • Polysaccharides / biosynthesis
  • Protein Processing, Post-Translational
  • Sialyltransferases / genetics*

Substances

  • Polysaccharides
  • Glycosyltransferases
  • B4GALT2 protein, human
  • Galactosyltransferases
  • N-Acetylglucosaminyltransferases
  • B3GNT2 protein, human
  • ST6GALNAC2 protein, human
  • Sialyltransferases