Abstract
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.
Highlights
Gliomas are located in the central nervous system and derive from glial cell precursors
As a first step to interrogate whether a differential profile of glycans is involved in the aggressiveness of glioma, we compared the expression of the Lewis glycan family (SLex, Lewis X (Lex), Sialyl Lewis A (SLea), Lewis A (Lea), Lewis Y (Ley) and Lewis B (Leb)) and truncated O-GalNAc glycans (Tn, STn and T) between high- and low-grade human glioma cell lines by flow cytometry
Glioma is a disease for which targeted therapies could offer new therapeutic opportunities, especially for high-grade gliomas that inevitably recur within 2–3 cm from the original lesion after standard therapy [33]
Summary
Gliomas are located in the central nervous system and derive from glial cell precursors They are classified by the World Health Organization (WHO) into four groups according to aggressiveness parameters, the grade IV or glioblastoma (GBM) being the most malignant subtype for which no cure is available [1]. Novel clinical options have been approved in the last years, about 50% of the patients do not survive the first year after diagnosis and only a meager 5% reach 5-year survival rates [2] In this scenario, research in glycobiology emerges as a promising niche to find novel targets for clinical application in glioma. Research in glycobiology emerges as a promising niche to find novel targets for clinical application in glioma Glycans, both alone and in conjugation with other macromolecules, are essential for the existence of all multicellular cells. Significant progress has been made in understanding the role of glycans in several cancer indications, the impact of glycosylation and the potential of glycans as therapeutic targets merit further study [4]
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