Terminally sialylated and fucosylated complex N-glycans are involved in the malignant behavior of high-grade glioma
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Hector A. Cuello1, Gretel M. Ferreira1, Cynthia A. Gulino1, Alejandro Gomez Toledo2, Valeria I. Segatori1 and Mariano R. Gabri1
1 Center for Molecular and Translational Oncology, Quilmes National University, Bernal, Buenos Aires Province, Argentina
2 Infection Medicine (BMC), Faculty of Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden
|Mariano R. Gabri,||email:||[email protected]|
Keywords: glioma; glioblastoma; Lewis glycans; histone acetylation; N-glycans
Received: August 29, 2020 Accepted: December 08, 2020 Published: December 29, 2020
Gliomas are the most common intracranial primary tumors, for which very few therapeutic options are available. The most malignant subtype is the glioblastoma, a disease associated with a 5-year survival rate lower than 5%. Given that research in glycobiology continues highlighting the role of glycans in tumor cell biology, it offers an interesting niche for the search of new therapeutic targets. In this study, we characterized aberrant glycosylation and its impact on cell biology over a broad panel of high- and low-grade glioma cell lines. Results show high expression of terminal Lewis glycans, mainly SLex, and overexpression of sialyl- and fucosyltransferases involved in their biosynthesis in high-grade glioma cell lines. Moreover, we report an association of complex multi-antennary N-glycans presenting β1,6-GlcNAc branches with the high-grade glioma cells, which also overexpressed the gene responsible for these assemblies, MGAT5. In addition, downmodulation of N-glycosylation by treatment with the inhibitors Tunicamycin/Swainsonine or MGAT5 silencing decreased SLex expression, adhesion and migration in high-grade glioma cells. In contrast, no significant changes in these cell capacities were observed in low-grade glioma after treatment with the N-glycosylation inhibitors. Furthermore, inhibition of histone deacetylases by Trichostatin A provoked an increase in the expression of SLex and its biosynthetic related glycosyltransferases in low-grade glioma cells. Our results describe that aggressive glioma cells show high expression of Lewis glycans anchored to complex multi-antennary N-glycans. This glycophenotype plays a key role in malignant cell behavior and is regulated by histone acetylation dependent mechanisms.
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