Terminally sialylated and fucosylated complex N-glycans are involved in the malignant behavior of high-grade glioma

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Terminally sialylated and fucosylated complex N-glycans are involved in the malignant behavior of high-grade glioma. / Cuello, Hector A.; Ferreira, Gretel M.; Gulino, Cynthia A.; Toledo, Alejandro Gomez; Segatori, Valeria I.; Gabri, Mariano R.

In: Oncotarget, Vol. 11, No. 35, 2021, p. 4822-4835.

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Cuello, Hector A. ; Ferreira, Gretel M. ; Gulino, Cynthia A. ; Toledo, Alejandro Gomez ; Segatori, Valeria I. ; Gabri, Mariano R. / Terminally sialylated and fucosylated complex N-glycans are involved in the malignant behavior of high-grade glioma. In: Oncotarget. 2021 ; Vol. 11, No. 35. pp. 4822-4835.

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TY - JOUR

T1 - Terminally sialylated and fucosylated complex N-glycans are involved in the malignant behavior of high-grade glioma

AU - Cuello, Hector A.

AU - Ferreira, Gretel M.

AU - Gulino, Cynthia A.

AU - Toledo, Alejandro Gomez

AU - Segatori, Valeria I.

AU - Gabri, Mariano R.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Glioblastoma

KW - Glioma

KW - Histone acetylation

KW - Lewis glycans

KW - N-glycans

U2 - 10.18632/ONCOTARGET.27850

DO - 10.18632/ONCOTARGET.27850

M3 - Article

AN - SCOPUS:85099906066

VL - 11

SP - 4822

EP - 4835

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 35

ER -