Protein Glycosylation in Cancer

Stowell, Sean R.; Ju, Tongzhong; Cummings, Richard D.

doi:10.1146/annurev-pathol-012414-040438

Cited by 652 publications

(576 citation statements)

References 277 publications

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“…Although the amount and type of carbohydrate chains are inconceivably huge, the type of elementary carbohydrate residues constituting diverse carbohydrate‐chains is fortunately limited, especially these in mammalian cells. Based on the core structures of N‐linked and O‐linked oligosaccharides,13 the common monosaccharide residues are the following ones:13 N‐acetyl‐D‐glucosamine (GlcNAc), N‐acetylgalactosamine (GalNAc), fucose (Fuc), mannose (Man), galactose (Gal), and sialic acid (Sia). Moreover, based on our related studies on carbohydrates6,14, 15, 16 we found the carbohydrates tended to form clusters as functional domains, where various functional glycocongujates locate via being cross‐linked by carbohydrate‐binding proteins (CBPs), with the contributions of lipid rafts as the stable factors and actin cytoskeletion as restricted factors.…”

Section: Introductionmentioning

confidence: 99%

Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super‐Resolution Fluorescence Imaging

et al. 2016

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Carbohydrate alterations on cell membranes are associated with various cancer processes, including tumorigenesis, malignant transformation, and tumor dissemination. However, variations in the distributions of cancer‐associated carbohydrates are unclear at the molecular level. Herein, direct stochastic optical reconstruction microscopy is used to reveal that seven major types of carbohydrates tended to form obvious clusters on cancer cell membranes compared with normal cell membranes (both cultured and primary cells), and most types of carbohydrates present a similar distributed characteristic on various cancer cells (e.g., HeLa and Os‐Rc‐2 cells). Significantly, sialic acid is found to distribute in larger‐sized clusters with a higher cluster coverage percentage on various cancer cells than normal cells. These findings on the aberrant distributions of cancer‐associated carbohydrates can potentially serve as novel diagnostic and therapeutic targets, as well as making a contribution to clarify how abnormal glycosylations of membrane glycoconjugates participate in tumorigenesis and metastasis.

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Section: Introductionmentioning

confidence: 99%

Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super‐Resolution Fluorescence Imaging

et al. 2016

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“…One such change typically seen in tumors is the alteration of protein glycosylation (1). In particular, changes in mucin-type O-linked glycosylation have been associated with cancer development and poor prognosis-and many diagnostic markers are based on these changes (1). Mucin-type O-linked glycosylation is initiated by a family of enzymes (known as the GalNAcTs 3 or ppGalNAcTs) that catalyze the addition of GalNAc onto the serine or threonine residues of proteins transiting the Golgi apparatus (Fig.…”

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confidence: 99%

“…However, in cancerous tissues, these structures are typically truncated, with many existing as only a single GalNAc (Tn antigen) or GalNAc capped with sialic acid (STn antigen) (1). The reasons for O-glycan truncation in cancerous tissues remain largely unknown, although many studies have implicated the enzymes involved in O-glycan extension in these alterations (1,3,4). Likewise, whether the changes in O-glycan structure are contributing to neoplastic transformation or are a by-product of the transformation process itself remains an ongoing area of inquiry.…”

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Pleiotropic effects of O-glycosylation in colon cancer

Zhang

Hagen

2018

Journal of Biological Chemistry

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Edited by Eric R. Fearon Changes in the O-glycosylation of proteins have long been associated with the development of cancer, but establishing causal relationships between altered glycosylation and cancer progression remains incomplete. In this study, the authors perform comparative analyses of the cellular phenotypes, transcriptional changes, and alterations in the glycoproteome in colon cancer cells that differentially express one glycosyltransferase. Their results provide a wealth of data on which future studies can be based.The search for factors involved in the development and progression of cancer has revealed a multitude of genetic, epigenetic, and phenotypic changes that distinguish malignant cells from their normal counterparts. One such change typically seen in tumors is the alteration of protein glycosylation (1). In particular, changes in mucin-type O-linked glycosylation have been associated with cancer development and poor prognosis-and many diagnostic markers are based on these changes (1). Mucin-type O-linked glycosylation is initiated by a family of enzymes (known as the GalNAcTs 3 or ppGalNAcTs) that catalyze the addition of GalNAc onto the serine or threonine residues of proteins transiting the Golgi apparatus (Fig. 1A) (2). In mammals, other enzymes add additional sugars to the extant GalNAc in a stepwise process to form what are known as core structures, which can then be further elongated and branched by other glycosyltransferases (Fig. 1A) (2). However, in cancerous tissues, these structures are typically truncated, with many existing as only a single GalNAc (Tn antigen) or GalNAc capped with sialic acid (STn antigen) (1). The reasons for O-glycan truncation in cancerous tissues remain largely unknown, although many studies have implicated the enzymes involved in O-glycan extension in these alterations (1,3,4). Likewise, whether the changes in O-glycan structure are contributing to neoplastic transformation or are a by-product of the transformation process itself remains an ongoing area of inquiry.In this issue of JBC, Wandall and colleagues (5) report new insights into the potential role of one member of the enzyme family that initiates O-linked glycosylation (GalNAc-T6) in the cellular transformations typically seen in cancerous cells and tissues. GalNAc-T6 is one of the 20 family members in mammals that are responsible for the initiation of O-linked glycosylation (2). Members of this family are essential in Drosophila and are involved in various cellular and developmental processes (6, 7). Aberrant GALNT6 expression has previously been observed in several cancer types, but the biological role of GALNT6 in vivo is still unknown.To initiate their study, Wandall and colleagues (5) examined the expression profiles for all 20 GALNT isoforms in 288 colon adenocarcinomas and 41 healthy colon samples, observing that GALNT6 expression is largely absent in healthy colon tissue but up-regulated in many colon adenocarcinomas. The authors then used the colon adenocarcinoma cell line LS174T (which...

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“…In addition, aberrant glycosylation is directly linked with many human diseases (4). Of note, glycans serve as useful biomarkers of various cancers and targets of therapeutic intervention (4)(5)(6)(7). Glycan binding proteins (GBPs) read the diversity and complexity of glycans in a relatively specific manner and execute the physiological or pathological information encoded by the polymers (1,8).…”

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Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

Zhang

Yang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glycans possess significant chemical diversity; glycan binding proteins (GBPs) recognize specific glycans to translate their structures to functions in various physiological and pathological processes. Therefore, the discovery and characterization of novel GBPs and characterization of glycan-GBP interactions are significant to provide potential targets for therapeutic intervention of many diseases. Here, we report the biochemical, functional, and structural characterization of a 130-amino-acid protein, Y3, from the mushroom Coprinus comatus. Biochemical studies of recombinant Y3 from a yeast expression system demonstrated the protein is a unique GBP. Additionally, we show that Y3 exhibits selective and potent cytotoxicity toward human T-cell leukemia Jurkat cells compared with a panel of cancer cell lines via inducing caspase-dependent apoptosis. Screening of a glycan array demonstrated GalNAcβ1-4(Fucα1-3)GlcNAc (LDNF) as a specific Y3-binding ligand. To provide a structural basis for function, the crystal structure was solved to a resolution of 1.2 Å, revealing a single-domain αβα-sandwich motif. Two monomers were dimerized to form a large 10-stranded, antiparallel β-sheet flanked by α-helices on each side, representing a unique oligomerization mode among GBPs. A large glycan binding pocket extends into the dimeric interface, and docking of LDNF identified key residues for glycan interactions. Disruption of residues predicted to be involved in LDNF/Y3 interactions resulted in the significant loss of binding to Jurkat T-cells and severely impaired their cytotoxicity. Collectively, these results demonstrate Y3 to be a GBP with selective cytotoxicity toward human T-cell leukemia cells and indicate its potential use in cancer diagnosis and treatment.

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Protein Glycosylation in Cancer

Cited by 652 publications

References 277 publications

Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super‐Resolution Fluorescence Imaging

Variation in Carbohydrates between Cancer and Normal Cell Membranes Revealed by Super‐Resolution Fluorescence Imaging

Pleiotropic effects of O-glycosylation in colon cancer

Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

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