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

Jenna Geddes Sweeney, Jennifer Liang, Aristotelis Antonopoulos, Nicholas Giovannone, Shuli Kang, Tony S. Mondala, Steven R. Head, Sandra L. King, Yoshihiko Tani, Danielle Brackett, Anne Dell, George F. Murphy, Stuart M. Haslam, Hans R. Widlund and Charles J. Dimitroff ()
Additional contact information
Jenna Geddes Sweeney: Brigham and Women’s Hospital
Jennifer Liang: Brigham and Women’s Hospital
Aristotelis Antonopoulos: Imperial College London, Division of Molecular Biosciences, Faculty of Natural Sciences
Nicholas Giovannone: Brigham and Women’s Hospital
Shuli Kang: The Scripps Research Institute
Tony S. Mondala: The Scripps Research Institute
Steven R. Head: The Scripps Research Institute
Sandra L. King: Brigham and Women’s Hospital
Yoshihiko Tani: Japanese Red Cross Kinki Block Blood Center
Danielle Brackett: Brigham and Women’s Hospital
Anne Dell: Imperial College London, Division of Molecular Biosciences, Faculty of Natural Sciences
George F. Murphy: Harvard Medical School
Stuart M. Haslam: Imperial College London, Division of Molecular Biosciences, Faculty of Natural Sciences
Hans R. Widlund: Brigham and Women’s Hospital
Charles J. Dimitroff: Brigham and Women’s Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05795-0

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