Modulation of glycosyltransferase ST6Gal-I in gastric cancer-derived organoids disrupts homeostatic epithelial cell turnover

J Biol Chem. 2020 Oct 9;295(41):14153-14163. doi: 10.1074/jbc.RA120.014887. Epub 2020 Aug 6.

Abstract

Programmed cell death promotes homeostatic cell turnover in the epithelium but is dysregulated in cancer. The glycosyltransferase ST6Gal-I is known to block homeostatic apoptosis through α2,6-linked sialylation of the death receptor TNFR1 in many cell types. However, its role has not been investigated in gastric epithelial cells or gastric tumorigenesis. We determined that human gastric antral epithelium rarely expressed ST6Gal-I, but the number of ST6Gal-I-expressing epithelial cells increased significantly with advancing premalignancy leading to cancer. The mRNA expression levels of ST6GAL-I and SOX9 in human gastric epithelial cells correlated positively with one another through the premalignancy cascade, indicating that increased epithelial cell expression of ST6Gal-I is associated with premalignant progression. To determine the functional impact of increased ST6Gal-I, we generated human gastric antral organoids from epithelial stem cells and differentiated epithelial monolayers from gastric organoids. Gastric epithelial stem cells strongly expressed ST6Gal-I, suggesting a novel biomarker of stemness. In contrast, organoid-derived epithelial monolayers expressed markedly reduced ST6Gal-I and underwent TNF-induced, caspase-mediated apoptosis, consistent with homeostasis. Conversely, epithelial monolayers generated from gastric cancer stem cells retained high levels of ST6Gal-I and resisted TNF-induced apoptosis, supporting prolonged survival. Protection from TNF-induced apoptosis depended on ST6Gal-I overexpression, because forced ST6Gal-I overexpression in normal gastric stem cell-differentiated monolayers inhibited TNF-induced apoptosis, and cleavage of α2,6-linked sialic acids from gastric cancer organoid-derived monolayers restored susceptibility to TNF-induced apoptosis. These findings implicate up-regulated ST6Gal-I expression in blocking homeostatic epithelial cell apoptosis in gastric cancer pathogenesis, suggesting a mechanism for prolonged epithelioid tumor cell survival.

Keywords: apoptosis; cancer biology; epithelial cell; gastric cancer; glycosylation; sialic acid; stem cells; stem cellsα-26-sialyltransferase 1 (ST6Gal-I); β-galactoside α2,6-sialyltransferase 1 (ST6GAL1).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / biosynthesis*
  • Antigens, CD / genetics
  • Cell Line
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Homeostasis*
  • Humans
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Organoids / metabolism*
  • Organoids / pathology
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Sialyltransferases / biosynthesis*
  • Sialyltransferases / genetics
  • Stomach Neoplasms / epidemiology*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Tumor Cells, Cultured

Substances

  • Antigens, CD
  • Neoplasm Proteins
  • SOX9 Transcription Factor
  • SOX9 protein, human
  • Sialyltransferases
  • ST6GAL1 protein, human