Journal Article

Loss of GCNT2/I-branched glycans enhances melanoma growth and survival

Dell, Anne, Mondala, Tony S., Head, Steven R., Haslam, Stuart M., Murphy, George F., Widlund, Hans R., Giovannone, Nicholas, King, Sandra L., Liang, Jennifer, Brackett, Danielle, Antonopoulos, Aristotelis, Dimitroff, Charles J., Sweeney, Jenna Geddes, Kang, Shuli, Tani, Yoshihiko

2018

Overview

Cancer cells often display altered cell-surface glycans compared to their nontransformed counterparts. However, functional contributions of glycans to cancer initiation and progression remain poorly understood. Here, from expression-based analyses across cancer lineages, we found that melanomas exhibit significant transcriptional changes in glycosylation-related genes. This gene signature revealed that, compared to normal melanocytes, melanomas downregulate I-branching glycosyltransferase, GCNT2, leading to a loss of cell-surface I-branched glycans. We found that GCNT2 inversely correlated with clinical progression and that loss of GCNT2 increased melanoma xenograft growth, promoted colony formation, and enhanced cell survival. Conversely, overexpression of GCNT2 decreased melanoma xenograft growth, inhibited colony formation, and increased cell death. More focused analyses revealed reduced signaling responses of two representative glycoprotein families modified by GCNT2, insulin-like growth factor receptor and integrins. Overall, these studies reveal how subtle changes in glycan structure can regulate several malignancy-associated pathways and alter melanoma signaling, growth, and survival. Aberrant glycosylation patterns on cancer cells promote several pro-tumorigenic functions, including enhancing tumor cell proliferation. Here the authors provide data that show melanoma cells downregulate GCNT2 with consequent loss of I-branched glycans; this leads to the formation of extended i-linear glycans and enhances melanoma growth via increases, in part, by IGF-1- and extracellular matrix-induced signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 38 / 45 / 631/80/221 / 64 / 64/60 / 692/4028/67/1813/1634 / 96 / Animals / Cancer / Cell death / Cell Line, Tumor / Cell surface / Cell survival / Cell Survival - genetics / Cell Survival - physiology / Colonies / Extracellular Matrix - genetics / Extracellular Matrix - metabolism / Glycan / Glycoproteins / Glycosylation / Glycosyltransferase / Growth factors / Humanities and Social Sciences / Humans / Insulin / Integrins / Malignancy / Melanocytes / Melanoma / Melanoma - genetics / Melanoma - metabolism / Melanoma - pathology / Mice / Mice, Knockout / multidisciplinary / N-Acetylglucosaminyltransferases - genetics / N-Acetylglucosaminyltransferases - metabolism / N-Acetylhexosaminyltransferases - genetics / N-Acetylhexosaminyltransferases - metabolism / Polysaccharides / Polysaccharides - metabolism / Receptors, Interleukin-2 - genetics / Receptors, Interleukin-2 - metabolism / Science / Science (multidisciplinary) / Signal Transduction - genetics / Signal Transduction - physiology / Signaling / Survival / Transcription / Xenografts / Xenotransplantation