Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

Abstract

Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes in cancer yields to cancer-specific alterations of glycoprotein sialylation. Mounting evidence indicate that hypersialylation is closely associated with cancer progression and metastatic spread, and can be of prognostic significance in human cancer. Aberrant sialylation is not only a result of cancer, but also a driver of malignant phenotype, directly impacting key processes such as tumor cell dissociation and invasion, cell-cell and cell-matrix interactions, angiogenesis, resistance to apoptosis, and evasion of immune destruction. In this review we provide insights on the impact of sialylation in tumor progression, and outline the possible application of sialyltransferases as cancer biomarkers. We also summarize the most promising findings on the development of sialyltransferase inhibitors as potential anti-cancer treatments.

Structural Insights in Mammalian Sialyltransferases and Fucosyltransferases: We Have Come a Long Way, but It Is Still a Long Way Down

“…The catalytic domain of all STs is characterized by four conserved peptide sequences, termed sialylmotifs: large (L), small (S), 3rd (III), and very small (VS) [27][28][29]. Human ST sequences have low sequence similarity but share 10 invariant residues-five in motif L, two in motif S and VS, and one in motif III [23,27]. Motif L is mainly engaged in binding donor substrates, while sialylmotifs S, III, and VS are involved in binding acceptor substrates or both substrates [23,27,30,31].…”

“…STs in mammals have been grouped into GT29 in the CAZy database ( Table 1 ). The cell sialylation status, which is determined by the extent and nature of sialic acid linkages, undergoes a transformation in cancer progression, which is correlated with the upregulation of sialyltransferases [ 17 , 19 , 21 , 22 , 23 ] ( Table 1 ).…”

“…Human ST sequences have low sequence similarity but share 10 invariant residues—five in motif L, two in motif S and VS, and one in motif III [ 23 , 27 ]. Motif L is mainly engaged in binding donor substrates, while sialylmotifs S, III, and VS are involved in binding acceptor substrates or both substrates [ 23 , 27 , 30 , 31 ]. Both L and S contain an invariant cysteine residue and participate in the formation of an intramolecular disulfide linkage essential for the active conformation of the enzyme [ 32 , 33 ].…”

“…The preferred site for fucosylation varies considerably among α1,2 and α-1,3/4 FUTs, which has a remarkable impact on the synthesis of terminally fucosylated epitopes, such as blood antigens (H1 and H2) and Lewis antigens (Le x , Le y , Le a , Le b , sLe x , and sLe a ), thus contributing toward the complexity of fucose-containing Lewis epitopes in naturally occurring glycoconjugates [ 24 , 44 ]. Pronounced over-expression of Lewis epitopes has been reported in the manifestation of cancer [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ] ( Table 1 ). SialylLewis (sLe x and sLe a ) epitopes are selectin ligands that are overexpressed in cancers due to the upregulation of FUT4, FUT5, FUT6, and FUT7 [ 45 ].…”

“…Sialyltransferases (STs) and fucosyltransferases (FUTs) are two distinct classes of GT in terms of structural fold architecture, substrate specificity, the nature of their interactions with both donor and acceptor substrates, and catalysis. Intriguingly, the dysregulation of both STs and FUTs results in the altered expression of sialylated and fucosylated epitopes, which are hallmarks of cancer cells [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. To date, their chemical biology and potential for drug discovery in cancer have been relatively unexplored [ 15 ].…”