Sialylation is involved in cell fate decision during development, reprogramming and cancer progression

Abstract

Sialylation, or the covalent addition of sialic acid to the terminal end of glycoproteins, is a biologically important modification that is involved in embryonic development, neurodevelopment, reprogramming, oncogenesis and immune responses. In this review, we have given a comprehensive overview of the current literature on the involvement of sialylation in cell fate decision during development, reprogramming and cancer progression. Sialylation is essential for early embryonic development and the deletion of UDP-GlcNAc 2-epimerase, a rate-limiting enzyme in sialic acid biosynthesis, is embryonically lethal. Furthermore, the sialyltransferase ST6GAL1 is required for somatic cell reprogramming, and its downregulation is associated with decreased reprogramming efficiency. In addition, sialylation levels and patterns are altered during cancer progression, indicating the potential of sialylated molecules as cancer biomarkers. Taken together, the current evidences demonstrate that sialylation is involved in crucial cell fate decision.

Keywords: cancer; cell fate; development; reprogramming; sialylation.

Figure 1

Structures of sialic acids and the diversity of sialylated glycoproteins. (A) Structures of sialic acids. Neu5Ac, Neu5Gc and Kdn are similarly structured and they possess different groups at the C5 position, which are red underlined. (B) The diversity of sialylated glycoproteins. Sialylated glycans can be attached to proteins or peptides through oxygen atom on serine/threonine or nitrogen atom on asparagine. And sialylated glycans can be linear or branched, comprised of multiple saccharides, including GlcNAc, GalNAc, mannose, fucose, galactose and so on

Figure 2

The biosynthesis pathway of sialylation. The nucleotide sugar UDP-GlcNAc, the production of hexosamine pathway, is converted into ManNAc by UDP-GlcNAc 2-epimerase (whose encoding gene is GNE in human). ManNAc is metabolic precursor for the synthesis of sialic acid and produces Neu5Ac in the cytosol, which then enters the nucleus to produce CMP-Neu5Ac. CMP-Neu5Ac are transported into Golgi where they are used by ST3GAL1-6, ST6GAL1-2/ST6GALNAC1-6, ST8SIA4 to produce α-2,3-, α-2,6- and α-2,8-linked sialoglycoproteins or gangliosides, respectively. Finally, sialosides are recycled by neuraminidases, regenerating sialic acid monomers that can be re-used

Figure 3

Sialic acid that on cell surface provides charge adhesion to positive cells (A) and charge repulsion to negative cells (B)

Figure 4

Sialylation is found to be aberrant in cancers compared to healthy controls, facilitating tumor growth and progression. In cancer cells, the proto-oncogene c-Myc, increase the expression of sialyltransferases (STs) in cancer cells. Therefore, the synthesis of sialylated glycans in the Golgi system by STs is enhanced. The aberrant high expression of sialylated glycans on Fas receptor (FasR) impairs the interaction between FasR and Fas, inhibiting apoptotic signaling transduction and preventing cancer cells from death. Moreover, increased sialylation on integrins can induce detachment from collagen, promoting cancer cell migration and tissue invasion. Cancer cell surfaces are enriched with glycans capped with SLX oligosaccharides which can interact with selectins, promoting cancer cells to adhere to and extravasate through the endothelium. Siglecs regulate immune surveillance of cancer and aberrant sialylation leads to Siglecs deficiency in cancer cells, preventing cancer cells from attack by immune system

Figure 5

The role of selectin-ligand binding in tumor metastasis. Activated endothelium secrets selectins, which mediate cancer cell rolling on the endothelium. Finally, the cancer cell migrates through the endothelium to other parts of the body