C1GALT1C1

Official Full Name

C1GALT1 specific chaperone 1

Organism

Homo sapiens

GeneID

29071

Background

This gene encodes a type II transmembrane protein that is similar to the core 1 beta1,3-galactosyltransferase 1, which catalyzes the synthesis of the core-1 structure, also known as Thomsen-Friedenreich antigen, on O-linked glycans. This gene product lacks the galactosyltransferase activity itself, but instead acts as a molecular chaperone required for the folding, stability and full activity of the core 1 beta1,3-galactosyltransferase 1. Mutations in this gene have been associated with Tn syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Dec 2009]

Synonyms

TNPS; AHUS8; COSMC; MST143; C1GALT2; HSPC067; C38H2-L1;

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Detailed Information

Recent Research Progress

The core 1β3GalT-specific molecular chaperone (COSMC) is located in X24 encoded by a single gene and acts as a specific molecular chaperone for T-synthase. The Tn antigen caused by mutations in the COSMC gene is one of the most common tumor-associated carbohydrate antigens. COSMC mutations have been observed in the autoimmune disease Tn syndrome and in some tumor cell lines. These findings demonstrate that Tn antigen (GalNAc-Ser/Thr) expression can be controlled by COSMC.

COSMC and PDAC

Human pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and fatal malignancies in the world and despite the tremendous efforts in research types of treatment remain limited. Often detected PDAC changes are truncated O-linked N-acetylgalactosamine (GalNAc) glycosylation with expression of the Tn antigen. Alterations in O-glycosylation affect the post-translationally modified O-GalNAc protein, leading to profound cellular changes. The Tn antigen is a tumor-associated glycan detected in 75-90% of PDAC and is detected up to 67% in its precursor lesions. Studies have found that Tn antigen expression was induced on various O-GalNAc glycoproteins in COSMC-deficient cell lines. Proliferation was reduced in COSMC knockdown cells, and migration was increased and apoptosis was reduced, highlighting the importance of Tn antigen expression for the transfer and anti-apoptotic behavior of PDAC-derived cells. Nucleolins were identified as O-GalNAc modified proteins in COSMC-deficient PDAC cell lines. Interestingly, immunohistochemical staining and co-localization studies of patient-derived PDAC showed that patients with strong co-localization of Tn antigen and nucleolin had lower survival rates. These findings confirmed the effect of altered O-glycan (Tn/STn) expression on the carcinogenic properties of pancreatic cancer and identify O-GalNAc-modified nucleolin as a new prognostic marker.

COSMC and IgAN

IgA nephropathy (IgAN) is one of the most common glomerular diseases leading to end-stage renal failure. The elevation of abnormal glycosylation of IgA1 is a key feature. Expression of a specific chaperone of COSMC is known to be reduced in IgAN. Recent studies have shown that hypermethylation of the COSMC promoter region may be a key mechanism for reducing the expression of COSMC mRNA in IgAN lymphocytes with associated increase in aberrantly glycosylated IgA1.

COSMC and IBD

Inflammatory bowel disease (IBD) is caused by abnormal immune stimulation against the genital mucosa, but relatively retained by the luminal microbiota and preferentially affects males in early onset disease. However, factors that lead to sex-specific risk and the pattern of dysbiosis are largely unexplored. COSMC encodes an important X-linked partner for glycocalyx formation and was recently identified as an IBD risk factor by genome-wide association studies. Matthew R et al. deleted COSMC in mouse intestinal epithelial cells (IECs) and found a significant reduction in microbial diversity in the progression from proximal to distal intestinal mucosa, but not in the overlying lumen, as seen in IBD. This loss of diversity was consistent with locally occurring pro-inflammatory lesions and distal intestinal limited pathology. In mechanism, COSMC regulates host genes, bacterial ligands, and nutrient availability to control microbial biogeography. Deletion of a COSMC allele (IEC- COSMC-/y) in males resulted in impaired mucus layer, spontaneous microbial-dependent inflammation and experimental colitis enhancement; however, females with loss of one allele and mosaic deletion of COSMC in 50% of crypts (IEC- COSMC^+/−) were protected from spontaneous inflammation and partially protected from experimental colitis, probably due to the normal migration of normal mucinglycocalyx from the wild-type (WT) cells to the knock-out (KO) crypt. These studies functionally validated COSMC as a risk factor for IBD and linked it to spatial patterns that regulate dysbiosis and gender bias in IBD.

COSMC and colon cancer

The expression of T antigen (Galbeta1) is associated with increased metastatic potential and poor prognosis in colorectal cancer. COSMC is a molecular chaperone required for the formation of active T-synthase, which catalyzes the synthesis of T antigens. However, the expression and role of COSMC in colorectal cancer remains unclear. Real-time PCR showed that overexpression of COSMC mRNA in colorectal tumors was associated with an increase in the tumor stage of the American Joint Committee on Cancer (AJCC) compared to paired non-tumor tissues. Forced expression of COSMC in HCT116 cells significantly increased T antigen expression and enhanced cell growth, migration and invasion, which was associated with increased phosphorylation of focal adhesion kinase (FAK), extracellular regulated protein kinases (ERK) and Protein Kinase B (Akt). These COSMC enhanced malignant phenotypes were significantly inhibited by specific inhibitors of MEK or PI3K. In addition, COSMC overexpression increased tumor growth and reduced survival of SCID mice bearing tumors. In contrast, knockdown of COSMC with Small interfering RNA (siRNA) in SW480 cells reduced malignant behavior and signaling pathways, which were essentially reversed by constitutively active Akt or MEK. In conclusion, these results suggest that COSMC promotes the malignant phenotype of colon cancer cells primarily by activating MEK/ERK and PI3K/Akt signaling pathways, and that COSMC may serve as a potential target for colorectal cancer therapy.

In conclusion, COSMC is critical for the formation of active core 1 synthetase, and mice lacking core 1 synthase or COSMC are embryonic lethal. COSMC is able to convert wild-type proteins into tumor-specific antigens by altering the glycosylation of proteins, which means that COSMC may be an important factor in regulating glycosylation and function of tumor cells.

References:

Qiang Sun, et al. DNA Methylation in Cosmc Promoter Region and Aberrantly Glycosylated IgA1 Associated with Pediatric IgA Nephropathy. Plos One, 2014.
Hofmann, et al. COSMC knockdown mediated aberrant O-glycosylation promotes oncogenic properties in pancreatic cancer. Molecular Cancer, 2015, 14:109 .
Kudelka MR, et al. Cosmc is an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk. Proceedings Of The National Academy Of Sciences Of The United States Of America, 2016, 113(51): 14787-14792.
Tongzhong Ju, et al. The Cosmc connection to the Tn antigen in cancer. Cancer Biomark. 2014, 14(1): 63–81.
John Huang, et al. The Molecular Chaperone Cosmc Enhances Malignant Behaviors of Colon Cancer Cells Via Activation of Akt and ERK. Molecular Carcinogenesis, 2014, 53: E62–E71 .

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