Aberrant O-glycosylation modulates aggressiveness in neuroblastoma

Abstract

Neuroblastoma (NB) is the most common pediatric malignancy diagnosed before the first birthday in which MYCN oncogene amplification is associated with poor prognosis. Although aberrant glycosylation is an important actor in cell biology, little is known about its role in pediatric cancers such as NB. In this work we characterized the glycophenotype and the enzyme expression involved in glycans biosynthesis in five established human NB cell lines and in patient-derived primary tumors with different MYCN status. Our results show a high expression of Lewis glycan family both in MYCN-amplified cell lines and patient samples. Additionally, we report that MYCN-amplified cells overexpressed Core 2-initiating glycosyltransferase C2GNT1 in association with specific ST3Gals and FUTs, and showed increased binding to E- and P- selectins. Silencing of C2GNT1 expression in NB cells diminished expression of Lewis glycans, decreased the E- and P-selectin binding, and reduced cell adhesion, migration and proliferation in vitro. Treatment of MYCN-non-amplified cells with Trichostatin A (TSA), an histone deacetylase inhibitor, increased the expression of Lewis glycans and the enzymes involved in their biosynthesis. Our results demonstrate that MYCN-amplified NB cells overexpress Lewis family glycans, which belong to the Core 2 O-glycans group. Their expression plays a key role in the malignant behaviour of the NB cells and it is modulated by epigenetic mechanisms.

The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

“…Furthermore, mice injected with ST3GAL6 knockdown MM cells demonstrated a decreased tumor burden and prolonged survival. Higher expression of Lewis antigens in neuroblastoma MYCN-amplified cell lines and patient samples could be a consequence of the overexpression of SiaTs, including ST3Gal3/4/6, compared to MYCN-non-amplified counterparts (110). Furthermore, high-grade glioma cell lines exhibit higher expression of terminal sLeX and of the SiaTs ST3Gal3/4/6 compared to low-grade glioma cells (111).…”

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

“…Both types of branching are potential scaffolds for such terminal assemblies as the Lewis glycans. Moreover, high expression of both core 2 O-GalNAc glycans and N-glycans bearing β1,6-GlcNAc branching has been associated with aggressiveness and tumor progression in several types of cancer [8,[18][19][20][21][22][23][24][25][26].…”

“…In particular, HDACs are related to repression of genes that encode proteins involved in tumorigenesis, specifically in control of cell growth, differentiation and apoptosis [ 7 ]. The association of HDACs with glycosylation patterns has been reported for cancer indications such as neuroblastoma and adrenocortical carcinoma [ 8 , 9 ].…”

Influence of glycosylation on the development and treatment of neuroblastoma.

“…6 MYCNamplified cell lines also have higher Lewis glycan expression profile. 8 These sugar moieties have been shown to enhance cell-cell interaction, assisting with the invasive nature and metastasis of neuroblastoma cancer cells. 9 The enzyme responsible for the Core 2 Structure of O-glycans, C2GNT1, was found to be highly expressed in MYCN-amplified cell lines.…”