Abstract 2435: ST6Gal-I sialylation potentiates hypoxia adaptation by enhancing HIF-1a signaling

Aberrant surface glycosylation is a well-known hallmark of a tumor cell, however the functional role of glycans in cancer cell biology remains unclear. Tumor cells frequently display an increase in surface α2-6 sialylation, a modification added to N-glycosylated proteins by the ST6Gal-I sialyltransferase. ST6Gal-I sialylates a select cohort of surface receptors, which correspondingly modulates receptor-induced intracellular signaling cascades. Emerging evidence suggests that ST6Gal-I-mediated sialylation promotes the survival of tumor cells exposed to a variety of cell stressors. In the current study we identify a new function for ST6Gal-I in protecting against hypoxic stress. In response to low oxygen tension, the hypoxia inducible factor, HIF-1α, becomes stabilized in tumor cells. In turn, HIF-1α stimulates the transcription of genes important for cell survival. To interrogate a role for ST6Gal-I in hypoxic response, we evaluated HIF-1α accumulation in ovarian and pancreatic cancer cells with ST6Gal-I overexpression or knockdown. We find that ST6Gal-I activity augments HIF-1α accumulation in cells treated with chemical hypoxia mimetics (DFO and DMOG), or alternatively grown in a hypoxic environment. Furthermore, hypoxic cells with high ST6Gal-I expression have increased mRNA levels of HIF-1α transcriptional targets including the glucose transporters, GLUT1 GLUT3, and the glycolytic enzyme, PDHK1. Interestingly, cells with high ST6Gal-I expression also have an increased pool of HIF-1α mRNA, suggesting that ST6Gal-I may influence the biosynthesis of HIF-1α. Finally, cells grown in hypoxia for several weeks display an enrichment in ST6Gal-I expression, consistent with the concept that ST6Gal-I acts as a pro-survival factor. Taken together, these findings highlight a novel, glycosylation-dependent mechanism that facilitates tumor cell adaptation to a hypoxic milieu.

Citation Format: Robert B. Jones, Kaitlyn A. Dorsett, Anita B. Hjelmeland, Susan L. Bellis. ST6Gal-I sialylation potentiates hypoxia adaptation by enhancing HIF-1a signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2435.