Aberrant cell surface glycosylation is prevalent in
tumor cells, and there is ample evidence that
glycans have functional roles in
carcinogenesis. Nonetheless, many molecular details remain unclear.
Tumor cells frequently exhibit increased α2-6 sialylation on N-
glycans, a modification that is added by the ST6Gal-I
sialyltransferase, and emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of
tumor cells exposed to various cell stressors. Here we report that ST6Gal-I protects
cancer cells from hypoxic stress. It is well known that
hypoxia-inducible factor 1α (HIF-1α) is stabilized in hypoxic cells, and, in turn, HIF-1α directs the transcription of genes important for cell survival. To investigate a putative role for ST6Gal-I in the hypoxic response, we examined HIF-1α accumulation in ovarian and
pancreatic cancer cells in ST6Gal-I overexpression or knockdown experiments. We found that ST6Gal-I activity augmented HIF-1α accumulation in cells grown in a hypoxic environment or treated with two chemical
hypoxia mimetics,
deferoxamine and
dimethyloxalylglycine. Correspondingly, hypoxic cells with high ST6Gal-I expression had increased
mRNA levels of HIF-1α transcriptional targets, including the
glucose transporter genes GLUT1 and GLUT3 and the glycolytic
enzyme gene PDHK1 Interestingly, high ST6Gal-I-expressing cells also had an increased pool of HIF-1α
mRNA, suggesting that ST6Gal-I may influence HIF-1α expression. Finally, cells grown in
hypoxia for several weeks displayed enriched ST6Gal-I expression, consistent with a pro-survival function. Taken together, these findings unravel a glycosylation-dependent mechanism that facilitates
tumor cell adaptation to a hypoxic milieu.