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C1galt1

Official Full Name
core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase, 1
Background
The protein encoded by this gene generates the common core 1 O-glycan structure, Gal-beta-1-3GalNAc-R, by the transfer of Gal from UDP-Gal to GalNAc-alpha-1-R. Core 1 is a precursor for many extended mucin-type O-glycans on cell surface and secreted glycoproteins. Studies in mice suggest that this gene plays a key role in thrombopoiesis and kidney homeostasis.
Synonyms
C1GALT1; core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase, 1; glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1; C1GALT; core 1 beta3 Gal T; T synthase; B3Gal-T8; core 1 beta3-Gal-T1; core 1 O-glycan T-synth; core 1 O-glycan T-synthase; core 1 beta1,3-galactosyltransferase 1; core1

Recent research progress

Abnormal glycosylation is often observed in cancers. The core 1 β 1, 3-galactosyltransferase (C1GALT1) is a proprietary enzyme in humans that catalyzes the biosynthesis of the core 1 O-glycan structure, Gal-GalNAc-O-Ser/Thr, whose expression is usually up-regulated during tumorigenesis. Recent studies have shown that C1GALT1 is often overexpressed in many cancers.

C1GALT1 and BC

Breast cancer (BC) is the most diagnosed malignancy among women with the highest cancer incidence reported worldwide. Public databases show that C1GALT1 mRNA and C1GALT1 protein are frequently up-regulated in breast cancer; and increased C1GALT1 expression is associated with higher histological grades and advanced tumor stage. Overexpression of C1GALT1 enhances breast cancer cell growth, migration, and invasion in vitro as well as tumor growth in vivo. In contrast, C1GALT1 knockdown inhibited these malignant phenotypes. Furthermore, C1GALT1 regulates the O-glycan structure on Mucin (MUC) 1 and promotes MUC1-C /β-catenin signaling in breast cancer cells. These findings indicate that C1GALT1 enhances malignant progression of breast cancer by promoting the MUC1-C/β-catenin signaling pathway. Revealing the function of C1GALT1 in breast cancer opens new insights into the role of C1GALT1 and O-glycosylation in tumorigenesis and renders the potential of C1GALT1 as a target of novel therapeutic agent development.

C1GALAT1 and colorectal tumors

Several studies have shown that C1GALT1 was frequently overexpressed in colorectal tumors and was associated with poor survival. Overexpression of C1GALT1 promotes cell survival, migration, invasion and sphere formation as well as tumor growth and metastasis of colon cancer cells. In contrast, knockdown of C1GALT1 with small interfering (si) RNA is sufficient to inhibit these malignant phenotypes in vitro and in vivo. In addition, Hung et al. demonstrated for the first time that fibroblast growth factor receptor (FGFR) 2 carries O-glycans in colon cancer cells. Mechanistic studies indicate that C1GALT1 alters O-glycans on FGFR2 and enhances bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. Moreover, BGF398 is a selective FGFR inhibitor that blocks the action of C1GALT1. These findings indicate that C1GALT1 overexpression can modify O-glycans on FGFR2 and enhance its phosphorylation, thereby promoting the invasion behavior and cancer stem cell-like properties in colon cancer cells, indicating a key role of O-glycosylation in the pathogenesis of colorectal cancer.

C1GALAT1 and HCC

Hepatocellular carcinoma (HCC) is one of the most aggressive tumors, making it the third leading cause of cancer death in the world. Most HCC treatment failures result from vascular invasion, metastasis, and recurrence after surgical resection. C1GALT1 has been reported to be overexpressed in HCC tumors, and its expression is associated with advanced tumor stage, metastasis and low survival. However, the underlying mechanism of C1GALT1 in HCC malignancies remains unclear. Recent studies have shown that overexpression of C1GALT1 enhances HCC cell adhesion to extracellular matrix (ECM) proteins, migration, and invasion, whereas RNAi-mediated knockdown of C1GALT1 suppressed these phenotypes. The promoting effect of C1GALT1 on HCC cell metastasis was confirmed in a mouse xenograft model. Mechanistic studies indicated that the C1GALT1-enhanced phenotypic changes in HCC cells were significantly suppressed by anti-integrin b1 blocking antibody. In addition, C1GALT1 was capable of modifying O-glycans on integrin b1 and modulating integrin b1 activity as well as its downstream signaling. These results indicate that C1GALT1 enhances HCC invasiveness through integrin b1 and provides new insights into the role of O-glycosylation in HCC metastasis.

C1GALAT1 and HNSCC

Head and neck squamous cell carcinoma (HNSCC) consists of squamous cell carcinoma arising in the oral cavity, oropharynx, hypopharynx, and larynx. C1GALT1 expression was shown to be up-regulated in HNSCC tumors and correlated with adverse clinical pathology features. In addition, high C1GALT1 expression predicted no disease and overall poor survival. Several studies have demonstrated that C1GALT1 expression is up-regulated in HNSCC tumors and is associated with adverse clinical pathology features. In addition, high C1GALT1 expression predicts poor disease-free and overall survivals. Overexpression of C1GALT1 enhances HNSCC cell viability, migration and invasion, which can be reversed by erlotinib. Silencing of C1GALT1 inhibits malignant both behavior in vitro and in vivo. Mass spectrometry and lectin pull-down assays demonstrate that C1GALT1 modified O-glycans on EGFR. Blocking O-glycan extension on EGFR by C1GALT1 knockdown reduces EGF-EGFR binding affinity and inhibits EGFR signaling, thereby inhibiting the malignant phenotype. Overall, the results demonstrate the pivotal role of O-glycosylation in the progression of HNSCC and highlight the therapeutic potential of targeting C1GALT1 in the treatment of HNSCC.

C1GALAT1 and ESCC

Esophagus squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors in the world, ranking sixth in cancer mortality and ninth in cancer incidence. Recent studies have found that C1GALT1 is associated with O-glycosylation MUC1 in ESCC. This finding not only suggests the diagnostic significance of C1GALT1 and MUC1 O-glycosylation in ESCC, but also opens up new insights into C1GALT1 and MUC1 O-glycosylation to inhibit ESCC cell metastasis in patients.

In conclusion, ClGALT1 plays an important role in many biological functions; and its altered expression leads to developmental defects and affects the malignant behavior of cancer. Therefore, further study of the detailed mechanism of C1GALT1 regulation of cancer behavior will provide new insights into the development of C1GALT1 as a therapeutic drug.

References:

  1. Chih-Hsing Chou, et al. Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway. Oncotarget, 2015, 6(8): 6123-6135.
  2. Hung JS, et al. C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2. Oncotarget, 2014, 5(8): 2096-2106.
  3. Liu CH, et al. C1GALT1 Promotes Invasive Phenotypes of Hepatocellular Carcinoma Cells by Modulating Integrin b1 Glycosylation and Activity. Plos One, 2014, 9(8): e94995.
  4. Lin Mei-Chun, et al. C1GALT1 predicts poor prognosis and is a potential therapeutic target in head and neck cancer. Oncogene, 2018.
  5. Wang Yuming, et al. Clinic implication of MUC1 O-glycosylation and C1GALT1 in esophagus squamous cell carcinoma. Science China. Life sciences, 2018.
  6. Bergstrom K, et al. Defective Intestinal Mucin-type O-glycosylation Causes Spontaneous Colitis-associated Cancer in Mice. Gastroenterology, 2016, 151: 1.
  7. Milde-Langosch K, et al. Relevance of βGal–βGalNAc-containing glycans and the enzymes involved in their synthesis for invasion and survival in breast cancer patients. Breast Cancer Research And Treatment, 2015, 151(3): 515-528.
  8. Bergstrom K, et al. Core 1- and core 3-derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice. Mucosal Immunology, 2017, 10(1): 91-103.

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