β-Galactoside α2,6-Sialyltranferase 1 Promotes Transforming Growth Factor-β-mediated Epithelial-Mesenchymal Transition

Lu, Jishun; Isaji, Tomoya; Im, Sanghun; Fukuda, Tomohiko; Hashii, Noritaka; Takakura, Daisuke; Kawasaki, Nana; Gu, Jianguo

doi:10.1074/jbc.m114.593392

Cited by 91 publications

(98 citation statements)

References 64 publications

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“…ST6GAL1 knock-out clearly inhibited cell migration as compared with parent cells (Fig. 4, E and F), which is consistent with the effects of ST6GAL1 knockdown we reported previously (29). Overexpression of GnT-III in this knock-out cells led to a further decrease in cell motility (Fig.…”

Section: High Expression Of St6gal1 Antagonizes the Anti-migratorysupporting

confidence: 80%

“…Our lab has reported that the presence of bisecting structures on E-cadherin may prolong its retention at the cell border (31), whereas overexpression of ST6GAL1 exerts the opposing effects (29). Further, knockdown of ST6GAL1 induced the expression of E-cadherin in several tumor cell lines (29). Therefore, it is conceivable that ST6GAL1 may counteract the antimetastatic role of GnT-III also through E-cadherin.…”

Section: Discussionmentioning

confidence: 99%

“…The disruption of E-cadherin-mediated cell adhesion appears to be a central event in the transition from noninvasive to invasive carcinomas (56). Our lab has reported that the presence of bisecting structures on E-cadherin may prolong its retention at the cell border (31), whereas overexpression of ST6GAL1 exerts the opposing effects (29). Further, knockdown of ST6GAL1 induced the expression of E-cadherin in several tumor cell lines (29).…”

Section: Discussionmentioning

confidence: 99%

“…The sequences of the primers used for the PCR amplification were designed previously (29). The GAPDH mRNA was used as a control in PCR runs, and the reaction products obtained were subjected to electrophoresis using 2% agarose gels containing ethidium bromide.…”

Section: Methodsmentioning

confidence: 99%

“…The membrane was incubated with a lectin for lectin blot analysis or with an antibody for immunoblot analysis. Immunoblotting was carried out as described previously (29). Proteins were separated by SDS-PAGE.…”

Section: Methodsmentioning

confidence: 99%

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Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

Isaji

et al. 2016

Journal of Biological Chemistry

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N-Acetylglucosaminyltransferase III (GnT-III), which catalyzes the addition of the bisecting GlcNAc branch on N-glycans, is usually described as a metastasis suppressor. Overexpression of GnT-III inhibited migration in multiple types of tumor cells. However, these results seem controversial to the clinical observations for the increased expression of GnT-III in human hepatomas, glioma, and ovarian cancers. Here, we present evidence that these inconsistencies are mainly attributed to the different expression pattern of cell sialylation. In detail, we show that overexpression of GnT-III significantly inhibits ␣2,3-sialylation but not ␣2,6-sialylation. The migratory ability of cells without or with a low level of ␣2,6-sialylation is consistently suppressed after GnT-III overexpression. In contrast, the effects of GnT-III overexpression are variable in tumor cells that are highly ␣2,6-sialylated. Overexpression of GnT-III promotes the cell migration in glioma cells U-251 and hepatoma cells HepG2, although it has little influence in human breast cancer cell MDA-MB-231 and gastric cancer cell MKN-45. Interestingly, up-regulation of ␣2,6-sialylation by overexpressing ␤-galactoside ␣2,6-sialyltranferase 1 in the ␣2,6-hyposialylated HeLa-S3 cells abolishes the anti-migratory effects of GnT-III. Conversely, depletion of ␣2,6-sialylation by knock-out of ␤-galactoside ␣2,6-sialyltranferase 1 in ␣2,6-hypersialylated HepG2 cells endows GnT-III with the anti-migratory ability. Taken together, our data clearly demonstrate that high expression of ␣2,6-sialylation on the cell surface could affect the anti-migratory role of GnT-III, which provides an insight into the mechanistic roles of GnT-III in tumor metastasis.Alterations in N-linked glycosylation have been observed in various malignant diseases such as cancer. Certain glycan structures resulting from the dysregulated glycosyltransferases and glycosidases are well known tumor markers and closely associated with the malignant progression (1). As examples, the ␣1,6-fucosylated ␣-fetoprotein catalyzed by ␣1,6-fucosyltransferase has been developed as a biomarker for primary hepatoma by Abelev (2). An increase in ␤1,6-GlcNAc branching of N-glycans as a consequence of enhanced expression of N-acetylglucosaminyltransferase V (GnT-V) 2 is convincingly correlated with the increased frequency of tumor metastasis (3-6). N-Acetylglucosaminyltransferase III (GnT-III) is one more important glycosyltransferase that has been receiving much attention for its involvement in the biology of tumor (7,8). It catalyzes the transfer of N-acetylglucosamine (GlcNAc) in a ␤1,4 linkage to mannose on N-glycans forming a bisecting GlcNAc structure. This step plays critical roles in determining the structure of N-glycans because introduction of the bisecting GlcNAc residue could preclude further processing and elongation of N-glycans, such as the formation of ␤1,6-GlcNAc branching structures (9). Considering also that overexpression of GnT-III inhibited the metastasis of multiple types of carcinomas (10, 1...

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Section: High Expression Of St6gal1 Antagonizes the Anti-migratorysupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

Isaji

et al. 2016

Journal of Biological Chemistry

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Specific N‐glycan alterations are coupled in epithelial–mesenchymal transition induced by EGF in GE11 epithelial cells

Wang³

et al. 2016

Cell Biology International

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Epithelial-mesenchymal transition (EMT) is a phenomenon in cancer progression during which cancer cells undergo remarkable alteration acquiring highly invasive property. The aim of this study was to evaluate specific N-glycan alterations during EMT induced by epidermal growth factor (EGF) in GE11 epithelial cells. Herein, we demonstrated that EGF activated epidermal growth factor receptor (EGFR)/Akt/extracellular signal-regulated kinase (ERK) phosphorylation and promoted GE11 cell proliferation. Meanwhile, EGF stimulated the epithelial cells to undergo morphological alteration, destroying cell-cell inter-contact and exhibiting mesenchymal cells higher metastatic potential. A wound-healing assay showed the migratory ability increased 1.5-fold after EGF treatment. Moreover, the relative intensity of N-cadherin versus E-cadherin increased 2.6-fold, and the E-cadherin distribution in cell-cell junctions became jagged and faint after EGF incubation for 72 h. Interestingly, the amounts of bisecting GlcNAc structure were dramatically declined, by contrast, the formation of β1,6 GlcNAc branches on cell surface was upregulated during EMT induced by EGF. To understand the roles of N-glycans in EGF-induced EMT, the cells were stably transfected with N-acetylglucosaminyltransferase III (GnT-III), which catalyzes the bisecting GlcNAc structure formation. As the markers for EMT, EGF-induced E-cadherin decrease and fibronectin increase were delayed in GnT-III-overexpressing cells. Taken together, these results demonstrated that specific N-glycan alterations were coupled in EMT induced by EGF, which might be contributed to diagnosis and therapy of tumor metastasis.

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Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

Carvalho-Cruz

Alisson-Silva

Todeschini

et al. 2017

Developmental Dynamics

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Epithelial to mesenchymal transition (EMT) is a developmental program reactivated by tumor cells that leads to the switch from epithelial to mesenchymal phenotype. During EMT, cells are transcriptionally regulated to decrease E-cadherin expression while expressing mesenchymal markers such as vimentin, fibronectin, and N-cadherin. Growing body of evidences suggest that cells engaged in EMT undergo a metabolic reprograming process, redirecting glucose flux toward hexosamine biosynthesis pathway (HBP), which fuels aberrant glycosylation patterns that are extensively observed in cancer cells. HBP depends on nutrient availability to produce its end product UDP-GlcNAc, and for this reason is considered a metabolic sensor pathway. UDP-GlcNAc is the substrate used for the synthesis of major types of glycosylation, including O-GlcNAc and cell surface glycans. In general, the rate limiting enzyme of HBP, GFAT, is overexpressed in many cancer types that present EMT features as well as aberrant glycosylation. Moreover, altered levels of O-GlcNAcylation can modulate cell morphology and favor EMT. In this review, we summarize some of the current knowledge that correlates glucose metabolism, aberrant glycosylation and hyper O-GlcNAcylation supported by HBP that leads to EMT activation. Developmental Dynamics 247:481-491, 2018. © 2017 Wiley Periodicals, Inc.

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β-Galactoside α2,6-Sialyltranferase 1 Promotes Transforming Growth Factor-β-mediated Epithelial-Mesenchymal Transition

Cited by 91 publications

References 64 publications

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

Specific N‐glycan alterations are coupled in epithelial–mesenchymal transition induced by EGF in GE11 epithelial cells

Cellular glycosylation senses metabolic changes and modulates cell plasticity during epithelial to mesenchymal transition

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