Significance of β-Galactoside α2,6 Sialyltranferase 1 in Cancers

Abstract

Altered glycosylation is a common feature of cancer cells. It takes a variety of forms, which includes loss of expression or excessive expression of some structures, the accumulation of precursors, the appearance of novel structures, etc. Notably, these changes in glycan structure do not occur as a random consequence of disorder biology. Only a limited subset of oligosaccharides is found frequently enriched on the tumor cell surface and implicated in different tumor phenotypes. Among these, altered sialylation has long been associated with metastatic cell behaviors such as invasion and enhanced cell survival and accumulating evidence points to the alteration occurring in the sialic acid linkage to other sugars, which normally exists in three main configurations: α2,3, α2,6, and α2,8, catalyzed by a group of sialyltransferases. The aberrant expression of all three configurations has been described in cancer progression. However, the increased α2,6 sialylation catalyzed by β-galactoside α2,6 sialyltranferase 1 (ST6Gal I) is frequently observed in many types of the cancers. In this review, we describe the findings on the role of ST6Gal I in cancer progression, and highlight in particular the knowledge of how ST6Gal I-mediated α2,6 sialylated glycans or sialylated carrier proteins regulate cell signaling to promote the malignant phenotype of human carcinoma.

Figure 1

α2,6 sialylation inhibits the galectin binding to the carbohydrate [11]. The free hydroxyl group on the six carbon of galactose is required for the binding to galectins [83]. The addition of α2,6 linked sialic acids at this site by sialyltransferases, therefore, could block their interaction. In contrast, α2,3 sialic acids have little effects on galectin binding.

Figure 2

Schematic representation of the regulation of α2,6 sialylation expression. The expression level of surface α2,6 sialylation is increased in tumors by several mechanisms. (1) Most commonly, ST6Gal I transcription is regulated by some transcription factors and methylation modification [18,31,32,33,34,35,36,37,101,130]; (2) Some factors like GOLPH3, recently, has been shown to interact with ST6Gal I, thereby modulating the efficiency of the sialylation [73]. (3) In addition, the expression levels of sialic acid transporter could affect α2,6 sialylation expression by regulating the donor substrate reservoir of ST6Gal I [118,119]; (4) The distribution as well as the amount of α2,6 sialic acids on cell surface also depend on the expression pattern of oligosaccharide acceptors [127,128,129]; (5) Further, as observed in many types of tumors, down-regulation of sialidases is usually accompanied by the upregulation of α2,6 sialylation expression [120,121,122,123,124].