The Cosmc connection to the Tn antigen in cancer

Abstract

The Tn antigen is a tumor-associated carbohydrate antigen that is not normally expressed in peripheral tissues or blood cells. Expression of this antigen, which is found in a majority of human carcinomas of all types, arises from a blockage in the normal O-glycosylation pathway in which glycans are extended from the common precursor GalNAcα1-O-Ser/Thr (Tn antigen). This precursor is generated in the Golgi apparatus on newly synthesized glycoproteins by a family of polypeptide αN-acetylgalactosaminyltransferases (ppGalNAcTs) and then extended to the common core 1 O-glycan Galβ1-3GalNAcα1-O-Ser/Thr (T antigen) by a single enzyme termed the T-synthase (core 1 β3-galactosyltransferase or C1GalT). Formation of the active form of the T-synthase requires a unique molecular chaperone termed Cosmc, encoded by Cosmc on the X-chromosome (Xq24 in humans, Xc3 in mice). Cosmc resides in the endoplasmic reticulum (ER) and prevents misfolding, aggregation, and proteasome-dependent degradation of newly synthesized T-synthase. Loss of expression of active T-synthase or Cosmc can lead to expression of the Tn antigen, along with its sialylated version Sialyl Tn antigen as observed in several cancers. Both genetic and epigenetic pathways, in addition to potential metabolic regulation, can result in abnormal expression of the Tn antigen. Engineered expression of the Tn antigen by disruption of either C1GalT (T-syn) or Cosmc in mice is associated with a tremendous range of pathologies and engineered expression of the Tn antigen in mouse embryos leads to embryonic death. Studies indicate that many membrane glycoproteins expressing the Tn antigen and/or truncated O-glycans may be dysfunctional, due to degradation and/or misfolding. Thus, expression of normal O-glycans is associated with health and homeostasis whereas truncation of O-glycans, e.g. the Tn and/or Sialyl Tn antigens is associated with cancer and other pathologies.

C-type lectin receptors in the control of T helper cell differentiation

“…IL-1β and IL-6 (humans), TGFβ (mice), and IL- 23 IL-6 and IL-27 . T-bet is the master regulator of T H 1 cell differentiation and is regulated by signal transducer and activator of transcription 4 (STAT4), which is induced by IL-12p70.…”

“…Malignant host cells also exhibit a distinct activation and/or expression of glycosyltransferases, often resulting in tumour-specific glycosylation patterns 23 . This makes CLRs well equipped to distinguish between different pathogens, to recognize tumour cells and to orchestrate the appropriate adaptive immune responses.…”

Hallmarks of glycosylation in cancer

“…Similarly, ectopic expression of the sialytransferase ST6GAL1 in breast cancer cells has been shown to reduce cell adhesion [94]. Cancer cells characteristically express proteins with truncated O-glycan structures that are thought to be due to mutations or epigenetic silencing of the COSMC gene [95, 96], or to increased expression of ST6GalNAc1 [88]. The immature O-glycophenotype of cancer cells has been directly linked to cancer cell growth and invasion [95].…”

Galectin-Binding O-Glycosylations as Regulators of Malignancy

“…The influence of ST6GalNAcs on cancer progression is most widely-recognized through their regulation of Tn and sTn antigens, which are considered biomarkers of cancer (3, 17, 41–43). Either elevated ST6GalNAc1 levels or compromised synthesis of T antigen via mutant Cosmic can raise sTn levels on cancer cells – a direct correlate of progression and poor prognosis (42–44).…”