Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex

Lee, Seung Ho; Hatakeyama, Shingo; Yu, Shin‐Yi; Bao, Xingfeng; Οhyama, Chikara; Khoo, Kay‐Hooi; Fukuda, Michiko N.; Fukuda, Minoru

doi:10.1074/jbc.m109.010934

Cited by 67 publications

(88 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine the presence of O-glycans in FXYD5, we treated cellular or surface proteins with a mixture of O-glycosidase and neuraminidase, which remove some but not all mucin-type O-glycans from glycoproteins (Fujikura et al, 2011). CD29 (β1 integrin), which is an N-and O-glycosylated protein (Clément et al, 2004;Lee et al, 2009), was used as the control for the glycosidase treatment (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Tokhtaeva

Sun

Deiss-Yehiely

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

FXYD5 (also known as dysadherin), a regulatory subunit of the Na,K-ATPase, impairs intercellular adhesion by a poorly understood mechanism. Here, we determined whether FXYD5 disrupts the transdimerization of Na,K-ATPase molecules located in neighboring cells. Mutagenesis of the Na,K-ATPase β 1 subunit identified four conserved residues, including Y199, that are crucial for the intercellular Na,K-ATPase trans-dimerization and adhesion. Modulation of expression of FXYD5 or of the β 1 subunit with intact or mutated β 1 -β 1 binding sites demonstrated that the anti-adhesive effect of FXYD5 depends on the presence of Y199 in the β 1 subunit. Immunodetection of the plasma membrane FXYD5 was prevented by the presence of O-glycans. Partial FXYD5 deglycosylation enabled antibody binding and showed that the protein level and the degree of O-glycosylation were greater in cancer than in normal cells. FXYD5-induced impairment of adhesion was abolished by both genetic and pharmacological inhibition of FXYD5 O-glycosylation. Therefore, the extracellular O-glycosylated domain of FXYD5 impairs adhesion by interfering with intercellular β 1 -β 1 interactions, suggesting that the ratio between FXYD5 and α 1 -β 1 heterodimer determines whether the Na,K-ATPase acts as a positive or negative regulator of intercellular adhesion.

show abstract

Section: Resultsmentioning

confidence: 99%

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Tokhtaeva

Sun

Deiss-Yehiely

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…Core3 O-glycan is synthesized by single glycosyltransferase, ␤3-N-acetylglucosaminyltransferase-6. Reduced core3 synthase 3 activity has been detected in malignant tumor cells (9,10), and we reported that increased core3 O-glycan structure negatively regulates tumorigenesis by regulating the function of ␣2␤1 integrin in prostate cancer (8).…”

mentioning

confidence: 99%

Core2 O-Glycan Structure Is Essential for the Cell Surface Expression of Sucrase Isomaltase and Dipeptidyl Peptidase-IV during Intestinal Cell Differentiation

Lee

Nakayama

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Alterations in glycosylation play an important role during intestinal cell differentiation. Here, we compared expression of mucin-type O-glycan synthases from proliferating and differentiated HT-29 and Caco-2 cells. Mucin-type O-glycan structures were analyzed at both stages by mass spectrometry. Core2 ␤1,6-N-acetylglucosaminyltransferase-2 (C2GnT-2) was markedly increased in differentiated HT-29 and Caco-2 cells, but the core3 structure was hardly detectable. To determine whether such differential expression of mucin-type O-glycan structures has physiological significance in intestinal cell differentiation, expression of sucrase isomaltase (SI) and dipeptidylpeptidase IV (DPP-IV), two well known intestinal differentiation markers, was examined. Interestingly, the fully glycosylated mature form of SI was decreased in C2GnT-2 knock-out mice but not in core2 N-acetylglucosaminyltransferase-3 (C2GnT-3) nulls. In addition, expression of SI and DPP-IV was dramatically reduced in C2GnT-1-3 triple knock-out mice. These patterns were confirmed by RNAi analysis; C2GnT-2 knockdown significantly reduced cell surface expression of SI and DPP-IV in Caco-2 cells. Similarly, overexpression of the core3 structure in HT-29 cells attenuated cell surface expression of both enzymes. These findings indicate that core3 O-glycan structure regulates cell surface expression of SI and DPP-IV and that core2 O-glycan is presumably an essential mucin-type O-glycan structure found in both molecules in vivo. Finally, goblet cells in the upper part of the crypt showed impaired maturation in the core2 O-glycan-deficient mice. These studies are the first to clearly identify functional mucin-type O-glycan structures modulating cell surface expression of SI and DPP-IV during the intestinal cell differentiation.

show abstract

“…In contrast, increase in b-1,6-GlcNAc branching on N-glycans by N-acetylglucosaminyltransferase V (GnT-V) enhances cell migration toward fibronectin and cell invasion (16). B3GNT6 (core3 synthase) adds core 3 O-glycan to a2 and b1-integrin subunits to suppress tumor formation and metastasis in prostate cancer (17). However, effects of B4GALT3 on the glycosylation and function of b1-integrin have not been reported.…”

Section: Introductionmentioning

confidence: 99%

β-1,4-Galactosyltransferase III Enhances Invasive Phenotypes Via β1-Integrin and Predicts Poor Prognosis in Neuroblastoma

Chang

Chen

Chou

et al. 2013

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Neuroblastoma (NB) is a neural crest-derived tumor that commonly occurs in childhood. b-1,4-Galactosyltransferase III (B4GALT3) is highly expressed in human fetal brain and is responsible for the generation of poly-N-acetyllactosamine, which plays a critical role in tumor progression. We therefore investigated the expression and role of B4GALT3 in NB.Experimental Design: We examined B4GALT3 expression in tumor specimens from 101 NB patients by immunohistochemistry and analyzed the correlation between B4GALT3 expression and clinicopathologic factors or survival. The functional role of B4GALT3 expression was investigated by overexpression or knockdown of B4GALT3 in NB cells for in vitro and in vivo studies.Results: We found that B4GALT3 expression correlated with advanced clinical stages (P ¼ 0.040), unfavorable Shimada histology (P < 0.001), and lower survival rate (P < 0.001). Multivariate analysis showed that B4GALT3 expression is an independent prognostic factor for poor survival of NB patients. B4GALT3 overexpression increased migration, invasion, and tumor growth of NB cells, whereas B4GALT3 knockdown suppressed the malignant phenotypes of NB cells. Mechanistic investigation showed that B4GALT3-enhanced migration and invasion were significantly suppressed by b1-integrin blocking antibody. Furthermore, B4GALT3 overexpression increased lactosamine glycans on b1-integrin, increased expression of mature b1-integrin via delayed degradation, and enhanced phosphorylation of focal adhesion kinase. Conversely, these properties were decreased by knockdown of B4GALT3 in NB cells.Conclusions: Our findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of b1-integrin in NB cells.

show abstract

Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex

Cited by 67 publications

References 46 publications

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

The O-glycosylated ectodomain of FXYD5 impairs adhesion by disrupting cell–cell trans-dimerization of Na,K-ATPase β1 subunits

Core2 O-Glycan Structure Is Essential for the Cell Surface Expression of Sucrase Isomaltase and Dipeptidyl Peptidase-IV during Intestinal Cell Differentiation

β-1,4-Galactosyltransferase III Enhances Invasive Phenotypes Via β1-Integrin and Predicts Poor Prognosis in Neuroblastoma

Contact Info

Product

Resources

About