The Role of Glycosylation in Melanoma Progression

Abstract

Malignant melanoma is the most aggressive form of skin cancer, which originates from the malignant transformation of melanocytes, the melanin-producing cells of the skin. Melanoma progression is typically described as a stepwise process in which metastasis formation ensues late during disease. A large body of evidence has shown that the accumulation of genetic and epigenetic alterations drives melanoma progression through the different steps. Mortality in melanoma is associated with metastatic disease. Accordingly, early-stage melanoma can be cured in the majority of cases by surgical excision, while late-stage melanoma is a highly lethal disease. Glycosylation is a post-translational modification that involves the transfer of glycosyl moieties to specific amino acid residues of proteins to form glycosidic bonds through the activity of glycosyltransferases. Aberrant glycosylation is considered a hallmark of cancer as it occurs in the majority of tumor types, including melanoma. The most widely occurring glycosylation changes in melanoma are represented by sialylation, fucosylation, and N- and I-glycan branching. In this review, we discuss the role of glycosylation in melanoma and provide insights on the mechanisms by which aberrant glycosylation promotes melanoma progression through activation of invasion and metastasis, immune evasion and cell proliferation.

Keywords: fucosylation; glycan branching; glycosylation; immune evasion; melanoma; metastasis; sialylation.

Figure 1

Glycosyltransferases as emerging effectors of melanoma progression. Schematic representation of selected glycosyltransferases and their role in the different stages of melanoma progression, based on the American Joint Committee on Cancer (AJCC) staging system. Stage I melanoma is no more than 1 mm thick; stage II extends beyond the epidermis into the thick dermis layer of the skin; stage III has metastasized to nearby lymph nodes, lymph vessels or skin; stage IV has metastasized to other places throughout the body, such as the brain, lungs or liver. Expression levels of FUT1/2, GCNT2 and GnT-III are high in early-stage and diminish during melanoma progression, whereas expression of FUT4/8, GCNT3, GnT-V, ST3GAL1, ST3GAL3 and ST6GAL1 are higher in late-stage melanomas. Glycosyltransferases may promote melanoma progression by several mechanisms: (1) interaction between Siglec1-expressing macrophages and metastatic cells facilitates metastatic colonization [21]; (2) loss of GCNT2 enhances growth factor receptor and integrin-mediated cell proliferation signaling pathways promoting melanoma growth and survival [22]; (3) Siglec-9/sialoligand interactions result in a tumor glycosylation-dependent circuit that suppresses CD8+ T cell effector responses in the tumor microenvironment [23]; (4) FUT8-mediated core fucosylation prevents L1CAM cleavage by plasmin, facilitating melanoma cell invasion [19]; (5) ST3GAL1 promotes melanoma metastasis through AXL [20]; (6) GnT-III represses metastasis through regulation of EGFR, integrins and cadherins [24,25,26]; (7) FUT4 regulates melanoma cell migration and invasion through activation of the PI3K/AKT signaling pathway [27]; (8) GCNT3 promotes melanoma cell migration and invasion through stabilization of MCAM [28]. See text for details regarding the role of the reported glycosyltransferases. Abbreviations used in the figure are listed in the “Abbreviation” section.