Increased susceptibility to colitis and colorectal tumors in mice lacking core 3–derived O-glycans

An, Guangyu; Wei, Bo; Xia, Baoyun; McDaniel, J. Michael; Ju, Tongzhong; Cummings, Richard D.; Braun, Jonathan; Xia, Lijun

doi:10.1084/jem.20061929

Cited by 298 publications

(287 citation statements)

References 64 publications

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“…It is known that mature O‐glycosylation depends specifically on T‐synthase activity and its single chaperone‐Cosmc 31. Besides, in colonic tissues, defective core 3 O‐glycosylation could also lead to the exposure of Tn antigen 21, 32. Here we found that the expression of C3GnT that controls core 3 O‐glycosylation in cancer tissues expressing Tn antigen (Tn‐positive) was comparable to that in Tn‐negative cancerous tissues, thereby suggesting that there were only possible defects in T‐synthase and/or Cosmc (Figure 2A).…”

Section: Resultsmentioning

confidence: 99%

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

Jiang

Liu

et al. 2018

J Cellular Molecular Medi

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Aberrant O‐glycosylation is frequently observed in colorectal cancer (CRC) patients, but it is unclear if it contributes intrinsically to tumorigenesis. Here, we investigated the biological consequences of aberrant O‐glycosylation in CRC. We first detected the expression profile of Tn antigen in a serial of human CRC tissues and then explored the genetic and biosynthetic mechanisms. Moreover, we used a human CRC cell line (LS174T), which express Tn antigen, to assess whether aberrant O‐glycosylation can directly promote oncogenic properties. It showed that Tn antigen was detected in around 86% human primary and metastatic CRC tissues. Bio‐functional investigations showed that T‐synthase and Cosmc were both impaired in cancer tissues. A further analysis detected an occurrence of hypermethylation of Cosmc gene, which possibly caused its loss‐of‐function and a consequent inactive T‐synthase. Transfection of LS174T cells with WT Cosmc restored mature O‐glycosylation, which subsequently down‐regulated cancer cell proliferation, migration and apoptotic‐resistant ability. Significantly, the expression of MUC2, a heavily O‐glycosylated glycoprotein that plays an essential role in intestinal function, was uniformly reduced in human CRC tissues as well as in LS174T cells. These data suggest that aberrant O‐glycosylation contributes to the development of CRC through direct induction of oncogenic properties in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

Jiang

Liu

et al. 2018

J Cellular Molecular Medi

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“…Additionally, these studies also identified O-glycans on mammalian Tango1/Mia3 (26,27), suggesting that O-glycans may perform similar protective functions to control secretion in mammalian systems. Indeed, alterations in both Tango1/Mia3 and O-glycosylation have been associated with diseases of the mammalian gastrointestinal tract (5,6,28,29), which are typically characterized by loss of secretion, loss of mucous membrane formation, and increased diffusion barrier permeability. Interestingly, PGANT4 is most similar to the mammalian ppGalNAc-T10 (8), which is abundantly expressed in the digestive system (30).…”

Section: Resultsmentioning

confidence: 99%

“…Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3)(4)(5)(6).…”

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confidence: 99%

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Zhang

Syed

Härd

et al. 2014

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

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Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.R egulation of secretory vesicle formation and polarized secretion in vivo is crucial to ensure the proper deposition of signaling molecules, morphogens, and matrix components that mediate growth and differentiation. Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3-6).Recent studies aimed at identifying the factors that influence secretion have elucidated novel proteins that function in unique aspects of secretion, including the enzymes responsible for the addition of sugars to mucins and other proteins (mucin-type O-glycosylation) (7). O-glycosylation is an essential, evolutionarily conserved protein modification (8, 9) that has direct medical relevance, as aberrations are responsible for the human diseases familial tumoral calcinosis (10, 11) and Tn syndrome (12). Loss of this protein modification affected constitutive secretion and Golgi apparatus structure in Drosophila cell culture (7, 13) and secretion in the developing respiratory system in vivo (14). Additionally, loss of O-glycosylation also disrupted secretion of an extracellular matrix protein (Tiggrin) in the developing wing, resulting in aberrant basement membrane formation and disrupted integrin-mediated cell adhesion (15). Mammalian studies have confirmed the effects of O-glycosylation on secretion, as loss of a glycosyltransferase (ppGalNAcT-1) disrupted secretion of laminin and collagen during mammalian organogenesis, altering the composition of the basement membrane and disrupting proper FGF signaling and organ growth (16). Although these studies all point to a role for O-glycosylation in se...

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“…Mucin dysfunction 33, 34 and JAM‐A deficiency 35, 36 have been shown to cause increased intestinal permeability, especially under basal conditions, with an enhanced susceptibility to experimental colitis. Thus, we evaluated mucin production in CerS2 null mice.…”

Section: Resultsmentioning

confidence: 99%

“…These two layers are organized into a net‐like polymer around mucin 2, the most abundant mucin protein, which is heavily glycosylated and secreted by goblet cells 33. Mucin can be detected by PAS and alcian blue staining (PAS detects neutral carbohydrates, whereas alcian blue recognizes acidic carbohydrates that represent sialylated, fucosylated or sulphated sugars 34). However, PAS and alcian blue staining were normal in the colon of CerS2 null mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

Kim

Volpert

Shin

et al. 2017

J Cellular Molecular Medi

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Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long‐chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very‐long acyl chain ceramides with concomitant increase of long chain bases and C16‐ceramides, were more susceptible to dextran sodium sulphate‐induced colitis, and their survival rate was markedly decreased compared with that of wild‐type littermates. Using mixed bone‐marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule‐A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. In vitro experiments using Caco‐2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2‐knockdown via CRISPR‐Cas9 technology impaired barrier function. In vivo myriocin administration, which normalized long‐chain bases and C16‐ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC‐dextran levels, indicating that altered SLs including deficiency of very‐long‐chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis.

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Increased susceptibility to colitis and colorectal tumors in mice lacking core 3–derived O-glycans

Cited by 298 publications

References 64 publications

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

Aberrant O‐glycosylation contributes to tumorigenesis in human colorectal cancer

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

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