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Review
. 2021 Dec 17:12:799861.
doi: 10.3389/fimmu.2021.799861. eCollection 2021.

The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

Marjolaine Hugonnet  1   2 , Pushpita Singh  1 , Quentin Haas  1 , Stephan von Gunten  1   2
Affiliations
Review

The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

Marjolaine Hugonnet et al. Front Immunol. .

Abstract

Aberrant glycosylation is a key feature of malignant transformation. Hypersialylation, the enhanced expression of sialic acid-terminated glycoconjugates on the cell surface, has been linked to immune evasion and metastatic spread, eventually by interaction with sialoglycan-binding lectins, including Siglecs and selectins. The biosynthesis of tumor-associated sialoglycans involves sialyltransferases, which are differentially expressed in cancer cells. In this review article, we provide an overview of the twenty human sialyltransferases and their roles in cancer biology and immunity. A better understanding of the individual contribution of select sialyltransferases to the tumor sialome may lead to more personalized strategies for the treatment of cancer.

Keywords: cancer; sialic acid; sialyltransferases; tumor glycosylation; tumor immunology.

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Conflict of interest statement

SVG received remuneration for serving on the scientific advisory board of Palleon Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Sialic acids. Sialic acids are nine-carbon monosaccharides. (A) The two main mammalian sialic acids N-acetyl neuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are shown. Neu5Gc is derived from Neu5Ac and differs by one oxygen atom in the N-glycolyl group, which is added by the enzyme cytidine monophosphate N-acetylneuraminic acid hydroxylase (CMAH) in the cytosol. Humans have an inactivating mutation of the CMAH gene and therefore they lack this enzymatic activity. (B) Kdn (2-keto-3-deoxy-D-glycero-D-galacto-nononic acid), which is more common among lower vertebrates and bacteria (see text).
Figure 2
Figure 2
Sialic acid metabolism in humans. CMP-Neu5Ac mostly occurs in the cytoplasm except of the CMP-sialic acid synthase (CMAS)-mediated reaction which takes place in the nucleus. UDP-GlcNAc-2 epimerase (GNE) synthesizes N-acetylmannosamine (ManNAc) in two steps. Then, Neu5Ac synthase (NANS) generates ManNAc-9-P, which is then dephosphorylated by Neu5Ac-P-phosphatase (NANP) to generate free sialic acid in the cytoplasm. The free sialic acid can enter the nucleus to be linked to CMP (cytidine-5’-monophosphate). The CMP-Neu5Ac is transferred to the Golgi apparatus via SLC35A1 transporter (solute carrier family 35 member A1), where it is used as a substrate for sialylation by different sialyltransferases (SiaT). Sialylated glycoconjugates are then exported to the cellular membrane or secreted. They can also be broken down by various neuraminidases (NEU1-4) present in different cellular localizations. The released sialic acid can reenter the biosynthesis pathway. Illustration by Aldona von Gunten.
Figure 3
Figure 3
Members of the four families of sialyltransferases catalyze different glycosidic linkages. (A) The four families of sialyltransferases as categorized according to restricted glycosidic linkage and acceptor specificity. Indicated are the transfer of activated CMP-Neu5Ac onto Gal, GalNAc or Neu5Ac moieties of carbohydrate chains (-R), such as on glycoproteins or glycolipids. (B) Examples of glycosidic α2,3, α2,6, and α2–8 -linkages involving the hydroxyl group at carbon atom 2 of Neu5Ac sialic acid with galactose (left, middle) or another sialic acid (right). CMP, cytidine monophosphate; Neu5Ac, N-acetylneuraminic acid; Gal, galactose; GalNAc, N-acetylgalactosamine.
Figure 4
Figure 4
Human sialyltransferases. The twenty human sialyltransferases listed according to their homology (60). Select generated oligosaccharides, preferred substrates and glycan specificities of individual sialyltransferases are shown.
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References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin (2018) 68:394–424. doi: 10.3322/caac.21492 - DOI - PubMed
    1. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer Genome Landscapes. Science (2013) 340:1546–58. doi: 10.1126/science.1235122 - DOI - PMC - PubMed
    1. Boligan KF, Mesa C, Fernandez LE, Von Gunten S. Cancer Intelligence Acquired (CIA): Tumor Glycosylation and Sialylation Codes Dismantling Antitumor Defense. Cell Mol Life Sci (2015) 72:1231–48. doi: 10.1007/s00018-014-1799-5 - DOI - PMC - PubMed
    1. Stowell SR, Ju T, Cummings RD. Protein Glycosylation in Cancer. Annu Rev Pathol Mech Dis (2015) 10:473–510. doi: 10.1146/annurev-pathol-012414-040438 - DOI - PMC - PubMed
    1. Oh-Uti K. Polysaccharides and a Glycidamin in the Tissue of Gastric Cancer. Tohoku J Exp Med (1949) 51:297–304. doi: 10.1620/tjem.51.297 - DOI

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