Expression of UDP-GalNAc:Polypeptide N-Acetylgalactosaminyltransferase-12 in Gastric and Colonic Cancer Cell Lines and in Human Colorectal Cancer

Guo, Jianming; Chen, Huili; Wang, Guomin; Zhang, Yongkang; Narimatsu, Hisashi

doi:10.1159/000081328

Cited by 31 publications

(22 citation statements)

References 58 publications

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“…Genetic screening of cancer patients is also revealing potential contributions of O-glycosylation pathways to cancer. For example, inherited deleterious variants in GALNT12 are associated with susceptibility to colorectal cancer [129], consistent with earlier studies that expression of GALNT12 seems to be a negative marker especially of metastatic gastric and colorectal cancer [130]. Somatic and germ-line mutations in GALNT12 have been identified in individuals with colon cancer [131].…”

Section: Tn and Stn Antigens In Colorectal Cancer (Crc)supporting

confidence: 79%

The Cosmc connection to the Tn antigen in cancer

Aryal

Kudelka

et al. 2014

CBM

127

125

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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.

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Section: Tn and Stn Antigens In Colorectal Cancer (Crc)supporting

confidence: 79%

The Cosmc connection to the Tn antigen in cancer

Aryal

Kudelka

et al. 2014

CBM

127

125

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“…Specific ppGalNAc Ts have also been linked to Williams-Beuren syndrome (WBSCR17, pt-GalNAc-T, or GALNTL3) (38,39) and hereditary multiple exostoses (ppGalNAc T5) (40). Genomewide sequencing studies have also revealed biochemically inactivating germ lines and somatic mutations in GALNT5 and GALNT12 (ppGalNAc T5 and T12) in individuals with breast and colon cancers (41,42) consistent with previous studies (43). Other genome-wide association scans suggest that GALNT2 (ppGalNAc T2) variants may be associated with levels of HDL cholesterol and coronary artery disease (44 -46).…”

supporting

confidence: 69%

Emerging Paradigms for the Initiation of Mucin-type Protein O-Glycosylation by the Polypeptide GalNAc Transferase Family of Glycosyltransferases

Gerken¹,

Jamison²,

Perrine³

et al. 2011

Journal of Biological Chemistry

143

160

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Mammalian mucin-type O-glycosylation is initiated by a large family of ϳ20 UDP-GalNAc:polypeptide ␣-N-acetylgalactosaminyltransferases (ppGalNAc Ts) that transfer ␣-GalNAc from UDP-GalNAc to Ser and Thr residues of polypeptide acceptors. Characterizing the peptide substrate specificity of each isoform is critical to understanding their properties, biological roles, and significance. Presently, only the specificities of ppGalNAc T1, T2, and T10 and the fly orthologues of T1 and T2 have been systematically characterized utilizing random peptide substrates. We now extend these studies to ppGalNAc T3, T5, and T12, transferases variously associated with human disease. Our results reveal several common features; the most striking is the similar pattern of enhancements for the three residues C-terminal to the site of glycosylation for those transferases that contain a common conserved Trp. In contrast, residues N-terminal to the site of glycosylation show a wide range of isoform-specific enhancements, with elevated preferences for Pro, Val, and Tyr being the most common at the ؊1 position. Further analysis reveals that the ratio of positive (Arg, Lys, and His) to negative (Asp and Glu) charged residue enhancements varied among transferases, thus further modulating substrate preference in an isoform-specific manner. By utilizing the obtained transferase-specific preferences, the glycosylation patterns of the ppGalNAc Ts against a series of peptide substrates could roughly be reproduced, demonstrating the potential for predicting isoform-specific glycosylation. We conclude that each ppGalNAc T isoform may be uniquely sensitive to peptide sequence and overall charge, which together dictates the substrate sites that will be glycosylated.Mucin-type O-glycosylation is one of the most common post-translational modifications of secreted and membrane-associated proteins. Glycoproteins containing O-glycosylated mucin domains serve many important biological roles chiefly because of their unique biophysical and structural properties that include an extended peptide conformation and robust resistance to proteases. Consequently, glycoproteins containing O-glycosylated mucin domains function in the protection of the cell surface, the modulation of cell-cell interactions, in the inflammatory and immune response, in metastasis and tumorigenesis, and in protein sorting, targeting, and turnover (for examples see Refs.

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“…It is well known that oncogenesis up-regulates the expression of N-glycans (13). In addition, ␣-fucosylation was observed in several types of tumors, including colorectal, hepatoma, ovarian, lung, and thyroid (52)(53)(54)(55)(56), and it is correlated with tumor metastasis, disease recurrence, and poor survival of patients (56). Together, our results show that changes in the glycophenotype observed during EMT are consistent with changes described in the literature; thus, EMT is an applicable model to study metabolic and glycophenotype changes during carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Mesenchymal Transition Induces Aberrant Glycosylation through Hexosamine Biosynthetic Pathway Activation

Lucena

Carvalho-Cruz

Donadio

et al. 2016

Journal of Biological Chemistry

105

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Deregulated cellular metabolism is a hallmark of tumors. Cancer cells increase glucose and glutamine flux to provide energy needs and macromolecular synthesis demands. Several studies have been focused on the importance of glycolysis and pentose phosphate pathway. However, a neglected but very important branch of glucose metabolism is the hexosamine biosynthesis pathway (HBP). The HBP is a branch of the glucose metabolic pathway that consumes ϳ2-5% of the total glucose, generating UDP-GlcNAc as the end product. UDP-GlcNAc is the donor substrate used in multiple glycosylation reactions. Thus, HBP links the altered metabolism with aberrant glycosylation providing a mechanism for cancer cells to sense and respond to microenvironment changes. Here, we investigate the changes of glucose metabolism during epithelial mesenchymal transition (EMT) and the role of O-GlcNAcylation in this process. We show that A549 cells increase glucose uptake during EMT, but instead of increasing the glycolysis and pentose phosphate pathway, the glucose is shunted through the HBP. The activation of HBP induces an aberrant cell surface glycosylation and O-GlcNAcylation. The cell surface glycans display an increase of sialylation ␣2-6, poly-LacNAc, and fucosylation, all known epitopes found in different tumor models. In addition, modulation of O-GlcNAc levels was demonstrated to be important during the EMT process. Taken together, our results indicate that EMT is an applicable model to study metabolic and glycophenotype changes during carcinogenesis, suggesting that cell glycosylation senses metabolic changes and modulates cell plasticity.Altered metabolism represents the first known difference between cancer cells and normal cells (1). The Warburg effect consists of an increase of glucose uptake for producing energy by a high rate of glycolysis followed by lactic acid fermentation even under high oxygen tension ("aerobic glycolysis"). Understanding the metabolism of tumors remains a topic of intense study with important therapeutic potential (2, 3). Several advances in cancer metabolism research over past years have enhanced our understanding of how aerobic glycolysis and other metabolic shifts support the anabolic demands of high growth rate (4). Traditionally, the study of glucose metabolism usually focused on the use of glucose for energy needs. However, cancer cells use glucose in anabolic pathways that provide precursors for the synthesis of lipids, proteins, glycans, and DNA to satisfy the demands of growth and proliferation. Several studies have been focused on the importance of the pentose phosphate pathway (PPP), 3 to generate NADPH that ensures the antioxidant defenses of the cell and to generate the nucleotides in high demand or the use of intermediates of the glycolytic pathway to generate molecules such as lipids or amino acids (5). However, a neglected but integral branch of glucose metabolism is the hexosamine biosynthesis pathway (HBP).Approximately 2-5% of glucose influx is directed to the HBP by the rate-limiting enzyme ...

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Expression of UDP-GalNAc:Polypeptide N-Acetylgalactosaminyltransferase-12 in Gastric and Colonic Cancer Cell Lines and in Human Colorectal Cancer

Cited by 31 publications

References 58 publications

The Cosmc connection to the Tn antigen in cancer

The Cosmc connection to the Tn antigen in cancer

Emerging Paradigms for the Initiation of Mucin-type Protein O-Glycosylation by the Polypeptide GalNAc Transferase Family of Glycosyltransferases

Epithelial Mesenchymal Transition Induces Aberrant Glycosylation through Hexosamine Biosynthetic Pathway Activation

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