ST8Sia6 sialylates CD44 in cancer cells to generate ligands for inhibitory Siglecs

Abstract Glycans decorate most proteins and lipids on the cell surface, and glycoproteins serve a critical role in cell-cell communication. The terminal modification of many glycans is a sialic acid. There are twenty mammalian sialyltransferases, each with a unique specificity. Recently, we demonstrated that the sialyltransferase ST8Sia6, which adds an alpha-2,8 linked sialic acid, generates ligands for the inhibitory receptor Siglec-E. ST8Sia6 overexpression accelerates tumor growth though inhibition of the immune response through Siglec-E. To understand the basis for ST8Sia6 function in tumors, proteomic analysis of murine tumor lines was performed to identify ST8Sia6 targets. Here, we demonstrate that ST8Sia6 sialylates CD44. Siglecs vary significantly across species, with the closest ortholog to murine Siglec-E is Siglec-7 in humans. We also show that ST8Sia6 sialylates CD44, generating ligands for Siglec-7. Thus, ST8Sia6 has a conserved role in both mice and humans to generate ligands for Siglecs. We also found that sialyltransferase ST6GalNac1 which adds an alpha-2,6 sialic acid to CD44, generating ligands for Siglec-7. The TCGA database showed synergistic effect of CD44 and ST8Sia6 decrease patient survival, while CD44 and ST6GalNac1 increases patient survival. Thus, CD44 is a target for ST8Sia6 and ST6GalNac1that generate ligand for inhibitory Siglecs, but the immunomodulatory effect may differ between two types of modifications, which is under current investigation.