Cuello Hector A, Ferreira Gretel M, Gulino Cynthia A, Toledo Alejandro Gomez, Segatori Valeria I, Gabri Mariano R
Center for Molecular and Translational Oncology, Quilmes National University, Bernal, Buenos Aires Province, Argentina.
Infection Medicine (BMC), Faculty of Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
Oncotarget. 2020 Dec 29;11(52):4822-4835. doi: 10.18632/oncotarget.27850.
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 SLe, 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 SLe 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 SLe 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.
神经胶质瘤是最常见的颅内原发性肿瘤，针对其的治疗选择非常有限。最恶性的亚型是胶质母细胞瘤，这种疾病的5年生存率低于5%。鉴于糖生物学研究不断凸显聚糖在肿瘤细胞生物学中的作用，它为寻找新的治疗靶点提供了一个有趣的领域。在本研究中，我们在一系列高等级和低等级神经胶质瘤细胞系中，对异常糖基化及其对细胞生物学的影响进行了表征。结果显示，在高等级神经胶质瘤细胞系中，末端Lewis聚糖（主要是SLe）高表达，且参与其生物合成的唾液酸转移酶和岩藻糖基转移酶过表达。此外，我们报告了呈现β1,6- GlcNAc分支的复杂多天线N-聚糖与高等级神经胶质瘤细胞相关，这些细胞也过表达负责这些组装的基因MGAT5。另外，用抑制剂衣霉素/苦马豆素处理或沉默MGAT5下调N-糖基化，会降低高等级神经胶质瘤细胞中SLe的表达、黏附及迁移能力。相比之下，用N-糖基化抑制剂处理低等级神经胶质瘤后，这些细胞能力未观察到显著变化。此外，曲古抑菌素A抑制组蛋白脱乙酰酶会导致低等级神经胶质瘤细胞中SLe及其生物合成相关糖基转移酶的表达增加。我们的结果表明，侵袭性神经胶质瘤细胞显示出锚定在复杂多天线N-聚糖上的Lewis聚糖高表达。这种糖表型在恶性细胞行为中起关键作用，并受组蛋白乙酰化依赖性机制调控。
