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C1GALT1 in health and disease.

ABSTRACT: O-linked glycosylation (O-glycosylation) and N-linked glycosylation (N-glycosylation) are the two most important forms of protein glycosylation, which is an important post-translational modification. The regulation of protein function involves numerous mechanisms, among which protein glycosylation is one of the most important. Core 1 synthase glycoprotein-N-acetylgalactosamine 3-β-galactosyltransferase 1 (C1GALT1) serves an important role in the regulation of O-glycosylation and is an essential enzyme for synthesizing the core 1 structure of mucin-type O-glycans. Furthermore, C1GALT1 serves a vital role in a number of biological functions, such as angiogenesis, platelet production and kidney development. Impaired C1GALT1 expression activity has been associated with different types of human diseases, including inflammatory or immune-mediated diseases, and cancer. O-glycosylation exists in normal tissues, as well as in tumor tissues. Previous studies have revealed that changes in the level of glycosyltransferase in different types of cancer may be used as potential therapeutic targets. Currently, numerous studies have reported the dual role of C1GALT1 in tumors (carcinogenesis and cancer suppression). The present review reports the role of C1GALT1 in normal development and human diseases. Since the mechanism and regulation of C1GALT1 and O-glycosylation remain elusive, further studies are required to elucidate their effects on development and disease.

SUBMITTER: Sun X

PROVIDER: S-EPMC8200938 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND & AIMS:Pancreatic ductal adenocarcinomas (PDACs) produce higher levels of truncated O-glycan structures (such as Tn and sTn) than normal pancreata. Dysregulated activity of core 1 synthase glycoprotein-N-acetylgalactosamine 3-?-galactosyltransferase 1 (C1GALT1) leads to increased expression of these truncated O-glycans. We investigated whether and how truncated O-glycans contributes to the development and progression of PDAC using mice with disruption of C1galt1. METHODS:We crossed C1galt1 floxed mice (C1galt1loxP/loxP) with KrasG12D/+; Trp53R172H/+; Pdx1-Cre (KPC) mice to create KPCC mice. Growth and progression of pancreatic tumors were compared between KPC and KPCC mice; pancreatic tissues were collected and analyzed by immunohistochemistry; immunofluorescence; and Sirius red, alcian blue, and lectin staining. We used the CRISPR/Cas9 system to disrupt C1GALT1 in human PDAC cells (T3M4 and CD18/HPAF) and levels of O-glycans were analyzed by lectin blotting, mass spectrometry, and lectin pulldown assay. Orthotopic studies and RNA sequencing analyses were performed with control and C1GALT1 knockout PDAC cells. C1GALT1 expression was analyzed in well-differentiated (n = 36) and poorly differentiated (n = 23) PDAC samples by immunohistochemistry. RESULTS:KPCC mice had significantly shorter survival times (median 102 days) than KPC mice (median 200 days) and developed early pancreatic intraepithelial neoplasias at 3 weeks, PDAC at 5 weeks, and metastasis at 10 weeks compared with KPC mice. Pancreatic tumors that developed in KPCC mice were more aggressive (more invasive and metastases) than those in KPC mice, had a decreased amount of stroma, and had increased production of Tn. Poorly differentiated PDAC specimens had significantly lower levels of C1GALT1 than well-differentiated PDACs. Human PDAC cells with knockout of C1GALT1 had aberrant glycosylation of MUC16 compared with control cells and increased expression of genes that regulate tumorigenesis and metastasis. CONCLUSIONS:In studies of KPC mice with disruption of C1galt1, we found that loss of C1galt1 promotes development of aggressive PDACs and increased metastasis. Knockout of C1galt1 leads to increased tumorigenicity and truncation of O-glycosylation on MUC16, which could contribute to increased aggressiveness.

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C1GALT1 in health and disease.

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