Posttranslational modification of E-cadherin by core fucosylation regulates Src activation and induces epithelial–mesenchymal transition-like process in lung cancer cells

Shao, Kang; Chen, Zhong Yi; Gautam, Suraj; Deng, Nian; Wu, Xingzhong

doi:10.1093/glycob/cwv089

Cited by 38 publications

(22 citation statements)

References 21 publications

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“…Deficient core fucosylation has been shown to alter receptor-mediated signaling in neurodevelopmental and cell signaling pathways known to be dysregulated in schizophrenia (Fukuda et al, 2011; Gu et al, 2013; Kurimoto et al, 2014; Shao et al, 2016; Vanhooren et al, 2011; Venkatachalam and Weinberg, 2013; Wang et al, 2006, 2005, 2015; Zhao et al, 2006). Based on findings in FUT8 −/− mice, it has been proposed that deficits of AMPAR-mediated signaling in schizophrenia could stem from abnormal α-1,6-fucosylation of glutamate receptor subunits by altering the stoichiometry and localization of intact AMPARs (Gu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia

Mueller

Yates

Haroutunian

et al. 2017

Schizophrenia Research

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Glycosylation is a post-translational modification that is an essential element in cell signaling and neurodevelopmental pathway regulation. Glycan attachment can influence the tertiary structure and molecular interactions of glycosylated substrates, adding an additional layer of regulatory complexity to functional mechanisms underlying central cell biological processes. One type of enzyme-mediated glycan attachment, fucosylation, can mediate glycoprotein and glycolipid cell surface expression, trafficking, secretion, and quality control to modulate a variety of inter- and intracellular signaling cascades. Building on prior reports of glycosylation abnormalities and evidence of dysregulated glycosylation enzyme expression in schizophrenia, we examined the protein expression of 5 key fucose-modifying enzymes: GDP-fucose:protein O-fucosyltransferase 1 (POFUT1), GDP-fucose:protein O-fucosyltransferase 2 (POFUT2), fucosyltransferase 8 (FUT8), fucosyltransferase 11 (FUT11), and plasma α-L-fucosidase (FUCA2) in postmortem superior temporal gyrus of schizophrenia (N = 16) and comparison (N = 14) subjects. We also used the fucose binding protein, Aleuria aurantia lectin (AAL), to assess α-1,6-fucosylated N-glycoprotein abundance in the same subjects. In schizophrenia we found increased expression of POFUT2, a fucosyltransferase uniquely responsible for O-fucosylation of thrombospondin-like repeat domains that is involved in a non-canonical endoplasmic reticulum quality control pathway. We also found decreased expression of FUT8 in schizophrenia. Given that FUT8 is the only α-1,6-fucosyltransferase expressed in mammals, the concurrent decrease in AAL binding in schizophrenia, particularly evident for N-glycoproteins in the ~52–58kDa and ~60–70kDa molecular mass ranges, likely reflects a consequence of abnormal FUT8 expression in the disorder. Dysregulated FUT8 and POFUT2 expression could potentially explain a variety of molecular abnormalities in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia

Mueller

Yates

Haroutunian

et al. 2017

Schizophrenia Research

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“…FUT8, the only enzyme that catalyzes α1,6-fucosylation in mammals, was up-regulated during EMT through transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1) ( 18 ). E-cadherin with enhanced core fucosylation (through FUT8 overexpression) in giant lung carcinoma cell line 95C reduced Src phosphorylation and inhibited cell migration, whereas E-cadherin with low core fucosylation activated Src and induced an EMT-like process ( 19 ). Increased expression of β-galactoside α2,6-sialyltranferase 1 (ST6GAL1), which adds terminal α2,6-sialylation to N-glycans, has been observed in a variety of carcinomas and in a TGF-β-induced EMT model.…”

Section: Role Of N-glycans In Emtmentioning

confidence: 99%

Role of Glycans in Cancer Cells Undergoing Epithelial–Mesenchymal Transition

Wang

Tan

et al. 2016

Front. Oncol.

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The term “cancer” refers to a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Epithelial–mesenchymal transition (EMT), a process whereby epithelial cells lose their cell polarity and cell–cell adhesion ability, and acquire migratory and invasive properties to gain mesenchymal phenotype, is an important step leading to tumor metastasis. Glycans, such as N-glycans, O-glycans, and glycosphingolipids, are involved in numerous biological processes, including inflammation, virus/bacteria–host interactions, cell–cell interactions, morphogenesis, and cancer development and progression. Aberrant expression of glycans has been observed in several EMT models, and the functional roles of such glycans in cancer development and progression has been investigated. We summarize here recent research progress regarding the functions of glycans in cancer cells undergoing EMT. Better understanding of the mechanisms underlying aberrant glycan patterns in EMT and cancer will facilitate the development of such glycans as cancer biomarkers or as targets in design and synthesis of anti-tumor drugs.

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“…More recently, emerging studies have suggested that posttranslational glycosylation modification of proteins plays a key role in altering protein functions, exerting profound effects on many important physiological and pathological processes, including cell growth, migration, and differentiation. [ 9 10 11 12 ] Core fucosylation (CF), which is catalyzed by α-1,6 fucosyltransferase (Fut8) in mammals,[ 13 ] is an important posttranslational glycosylation found to play a crucial role in pathological processes, including emphysema,[ 14 15 16 ] schizophrenia,[ 17 18 ] and hepatocellular carcinoma. [ 19 ] We recently demonstrated that diminishing the CF of transforming growth factor-β (TGF-β) receptors (TGF-βRs) blocked renal tubular EMT in cultured human renal proximal tubular epithelial cells in vitro and alleviated renal interstitial fibrosis in rats with unilateral ureteral obstruction.…”

Section: Introductionmentioning

confidence: 99%

Blocking Posttranslational Core Fucosylation Ameliorates Rat Peritoneal Mesothelial Cell Epithelial-Mesenchymal Transition

Wang

et al. 2017

Chinese Medical Journal

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Background:Core fucosylation (CF), catalyzed by α-1,6 fucosyltransferase (Fut8) in mammals, plays an important role in pathological processes through posttranslational modification of key signaling receptor proteins, including transforming growth factor (TGF)-β receptors and platelet-derived growth factor (PDGF) receptors. However, its effect on peritoneal fibrosis is unknown. Here, we investigated its influence on epithelial-mesenchymal transition (EMT) of rat peritoneal mesothelial cells (PMCs) in vitro induced by a high-glucose (HG) culture solution.Methods:Rat PMCs were first cultured in a HG (2.5%) culture solution to observe the CF expression level (fluorescein isothiocyanate-lens culinaris agglutinin), we next established a knockdown model of rat PMCs in vitro with Fut8 small interfering RNA (siRNA) to observe whether inhibiting CF decreases the messenger RNA (mRNA) expression and protein expression of Fut8 and reverses EMT status. Rat PMCs were randomly divided into control group, mock group (transfected with scrambled siRNA), Fut8 siRNA group, HG group, HG + mock group, and HG + Fut8 siRNA group. Finally, we examined the activation of TGF-β/Smad2/3 signaling and PDGF/extracellular signal-regulated kinase (ERK) signaling to observe the influence of CF on them.Results:CF, Fut8 mRNA, and protein expression were all significantly upregulated in HG- induced EMT model than those in the control rat PMCs (P < 0.05). Fut8 siRNA successfully blocked CF of TGF-β receptors and PDGF receptors and attenuated the EMT status (E-cadherin and α-SMA and phenotypic changes) in HG-induced rat PMCs. In TGF-β/Smad2/3 signaling, Fut8 siRNA did not suppress the protein expression of TGF-β receptors and Smad2/3; however, it significantly suppressed the phosphorylation of Smad2/3 (relative expression folds of HG + Fut8 group vs. HG group: 7.6 ± 0.4 vs. 15.1 ± 0.6, respectively, P < 0.05). In PDGF/ERK signaling, Fut8 siRNA did not suppress the protein expression of PDGF receptors and ERK, but it significantly suppressed the phosphorylation of ERK (relative expression folds of HG + Fut8 group vs. HG group: 8.7 ± 0.9 vs. 15.6 ± 1.2, respectively, P < 0.05). Blocking CF inactivated the activities of TGF-β and PDGF signaling pathways, and subsequently blocked EMT.Conclusions:These results demonstrate that CF contributes to rat PMC EMT, and that blocking it attenuates EMT. CF regulation is a potential therapeutic target of peritoneal fibrosis.

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Posttranslational modification of E-cadherin by core fucosylation regulates Src activation and induces epithelial–mesenchymal transition-like process in lung cancer cells

Cited by 38 publications

References 21 publications

Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia

Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia

Role of Glycans in Cancer Cells Undergoing Epithelial–Mesenchymal Transition

Blocking Posttranslational Core Fucosylation Ameliorates Rat Peritoneal Mesothelial Cell Epithelial-Mesenchymal Transition

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