Short O-GalNAc glycans: regulation and role in tumor development and clinical perspectives

• Published in: Biochimica et biophysica acta Vol. 1860; no. 8; pp. 1623 - 1639
• Main Authors: Chia, Joanne, Goh, Germaine, Bard, Frederic
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2016
• Subjects: Animals; antibodies; antigens; Antigens, Tumor-Associated, Carbohydrate - genetics; Antigens, Tumor-Associated, Carbohydrate - metabolism; biomarkers; Cancer; Cancer Vaccines - therapeutic use; cell membranes; enzymes; Galactosamine - genetics; Galactosamine - metabolism; GALNTs; genetic engineering; Glycoproteins - genetics; Glycoproteins - metabolism; Glycosylation; Humans; medicine; Membrane trafficking; neoplasm cells; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; neoplasms; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - therapy; O-GalNAc glycosylation; Oligosaccharides - genetics; Oligosaccharides - metabolism; physiological transport; polysaccharides; vaccine development; O-GalNAc glycosylation; Tn antigen; GALA pathway; GALNTs; C1GALT1; S-TF; EMT; GalNAc; S-Tn; ppGalNAcT (GALNT); sLex; Membrane trafficking; TF antigen; Cancer
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.03.008

While the underlying causes of cancer are genetic modifications, changes in cellular states mediate cancer development. Tumor cells display markedly changed glycosylation states, of which the O-GalNAc glycans called the Tn and TF antigens are particularly common. How these antigens get over-expressed is not clear. The expression levels of glycosylation enzymes fail to explain it. We describe the regulation of O-GalNAc glycosylation initiation and extension with emphasis on the initiating enzymes ppGalNAcTs (GALNTs), and introduce the GALA pathway — a change in GALNTs compartmentation within the secretory pathway that regulates Tn levels. We discuss the roles of O-GalNAc glycans and GALNTs in tumorigenic processes and finally consider diagnostic and therapeutic perspectives. Contrary to a common hypothesis, short O-glycans in tumors are not the result of an incomplete glycosylation process but rather reveal the activation of regulatory pathways. Surprisingly, high Tn levels reveal a major shift in the O-glycoproteome rather than a shortening of O-glycans. These changes are driven by membrane trafficking events. Many attempts to use O-glycans for biomarker, antibody and therapeutic vaccine development have been made, but suffer limitations including poor sensitivity and/or specificity that may in part derive from lack of a mechanistic understanding. Deciphering how short O-GalNAc glycans are regulated would open new perspectives to exploit this biology for therapeutic usage. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. •Tumor cells often upregulate the O-GalNAc glycans named Tn and TF antigens, whose levels correlate with poor prognosis.•Upregulation of O-GalNAc glycosylation initiation by GALNT enzyme relocation from Golgi to ER causes high Tn levels.•Diverse molecular mechanisms involving O-GalNAc glycans could play key roles in tumor invasiveness and cancer progression.•A better understanding how O-GalNAc glycans are regulated would facilitate the development of therapeutics.