DNA hypomethylation upregulates expression of the MGAT3 gene in HepG2 cells and leads to changes in N-glycosylation of secreted glycoproteins

Klasić, Marija; Krištić, Jasminka; Korać, Petra; Horvat, Tomislav; Markulin, Dora; Vojta, Aleksandar; Reiding, Karli R.; Wuhrer, Manfred; Lauc, Gordan; Zoldoš, Vlatka

doi:10.1038/srep24363

Cited by 25 publications

(11 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, the relevance in AD and cancer was shown using Mgat3 -/mice (4,17), and the absence of GnT-III results in various functional alterations of target proteins in vivo. Furthermore, in some cancer cells, aberrant upregulation of the MGAT3 gene and bisecting GlcNAc was reported (66,67), which is suggested to cause poor clinical outcomes. Currently, these bisecting GlcNAc-related phenotypes have been mainly considered as the direct consequences of the presence or absence of the bisecting GlcNAc residue itself, but some of these phenotypes could be caused by secondary effects on other parts of N-glycans, such as Le-fucosylation, sialylation and synthesis of other terminal epitopes.…”

Section: Discussionmentioning

confidence: 99%

Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan*[S]

Nakano

Mishra

Tokoro

et al. 2019

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Glycoproteins are decorated with complex glycans for protein functions. However, regulation mechanisms of complex glycan biosynthesis are largely unclear. Here we found that bisecting GlcNAc, a branching sugar residue in N-glycan, suppresses the biosynthesis of various types of terminal epitopes in N-glycans, including fucose, sialic acid and human natural killer-1. Expression of these epitopes in N-glycan was elevated in mice lacking the biosynthetic enzyme of bisecting GlcNAc, GnT-III, and was conversely suppressed by GnT-III overexpression in cells. Many glycosyltransferases for N-glycan terminals were revealed to prefer a nonbisected N-glycan as a substrate to its bisected counterpart, whereas no up-regulation of their mRNAs was found. This indicates that the elevated expression of the terminal N-glycan epitopes in GnT-III-deficient mice is attributed to the substrate specificity of the biosynthetic enzymes. Molecular dynamics simulations further confirmed that nonbisected glycans were preferentially accepted by those glycosyltransferases. These findings unveil a new regulation mechanism of protein N-glycosylation.

show abstract

Section: Discussionmentioning

confidence: 99%

Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan*[S]

Nakano

Mishra

Tokoro

et al. 2019

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…Indeed, while growth rate is slowed by HDAC inhibitor treatment in nearly all cancer cells, many also increase oncogenic properties such as increased motility and invasive capacity [9]. Although other epigenetic regulators, such as the DNA methyltransferase inhibitor 5-Aza-dc, have been used extensively in multiple cancer types to effectively target glycogenes and glycosylation enzymes to slow tumor progression [10–12], the effects of HDAC inhibitors on glycosylation, oncogenic phenotype, and chemotherapeutic response have not been extensively investigated. At a broader level, even though epigenetic regulation determines many aspects of oncogenesis and normal cellular behavior, these epigenetic processes and their regulation are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Alterations in the glycome after HDAC inhibition impact oncogenic potential in epigenetically plastic SW13 cells

Montgomery

Hull

2019

BMC Cancer

View full text Add to dashboard Cite

BackgroundDefects in the type and degree of cellular glycosylation impact oncogenesis on multiple levels. Although the type of glycosylation is determined by protein sequence encoded by the genome, the extent and modifications of glycosylation depends on the activity of biosynthetic enzymes and recent data suggests that the glycome is also subject to epigenetic regulation. This study focuses on the ability of HDAC inhibition to alter glycosylation and to lead to pro-oncogenic alterations in the glycome as assessed by metastatic potential and chemoresistance.MethodsEpigenetically plastic SW13 adrenocortical carcinoma cells were treated with FK228, an HDAC inhibitor with high affinity for HDAC1 and, to a lesser extent, HDAC2. In comparing HDAC inhibitor treated and control cells, differential expression of glycome-related genes were assessed by microarray. Differential glycosylation was then assessed by lectin binding arrays and the ability of cellular proteins to bind to glycans was assessed by glycan binding arrays. Differential sensitivity to paclitaxel, proliferation, and MMP activity were also assessed.ResultsTreatment with FK228 alters expression of enzymes in the biosynthetic pathways for a large number of glycome related genes including enzymes in all major glycosylation pathways and several glycan binding proteins. 84% of these differentially expressed glycome-related genes are linked to cancer, some as prognostic markers and others contributing basic oncogenic functions such as metastasis or chemoresistance. Glycan binding proteins also appear to be differentially expressed as protein extracts from treated and untreated cells show differential binding to glycan arrays. The impact of differential mRNA expression of glycosylation enzymes was documented by differential lectin binding. However, the assessment of changes in the glycome is complicated by the fact that detection of differential glycosylation through lectin binding is dependent on the methods used to prepare samples as protein-rich lysates show different binding than fixed cells in several cases. Paralleling the alterations in the glycome, treatment of SW13 cells with FK228 increases metastatic potential and reduces sensitivity to paclitaxel.ConclusionsThe glycome is substantially altered by HDAC inhibition and these changes may have far-reaching impacts on oncogenesis.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5129-4) contains supplementary material, which is available to authorized users.

show abstract

“…Dall’Olio et al highlighted that glycosylation is both under the control of epigenetic mechanisms and is an integral part of the epigenetic code ( Dall’Olio and Trinchera, 2017 ). Klasic et al showed that DNA hypomethylation up-regulated expression of the MGAT3 gene in HepG2 cells and led to changes in N -glycosylation of secreted glycoproteins ( Klasic et al, 2016 ). Chakraborty et al and Saldova et al highlighted the role that epigenetics (methylation) plays in glycosylation patterns ( Chachadi et al, 2011 ; Saldova et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated Glycosylation Patterns of Glycoproteins and DNA Methylation Landscapes in Mammalian Oogenesis and Preimplantation Embryo Development

Wang

Tian

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Glycosylation is one of the most fundamental post-translational modifications. However, the glycosylation patterns of glycoproteins have not been analyzed in mammalian preimplantation embryos, because of technical difficulties and scarcity of the required materials. Using high-throughput lectin microarrays of low-input cells and electrochemical techniques, an integration analysis of the DNA methylation and glycosylation landscapes of mammal oogenesis and preimplantation embryo development was performed. Highly noticeable changes occurred in the level of protein glycosylation during these events. Further analysis identified several stagespecific lectins including LEL, MNA-M, and MAL I. It was later confirmed that LEL was involved in mammalian oogenesis and preimplantation embryogenesis, and might be a marker of FGSC differentiation. Modified nanocomposite polyaniline/AuNPs were characterized by electron microscopy and modification on bare gold electrodes using layer-by-layer assembly technology. These nanoparticles were further subjected to accuracy measurements by analyzing the protein level of ten-eleven translocation protein (TET), which is an important enzyme in DNA demethylation that is regulated by O-glycosylation. Subsequent results showed that the variations in the glycosylation patterns of glycoproteins were opposite to those of the TET levels. Moreover, analysis of correlation between the changes in glyco-gene expression and female germline stem cell glycosylation profiles indicated that glycosylation was related to DNA methylation. Subsequent integration analysis showed that the trend in the variations of glycosylation patterns of glycoproteins was similar to that of DNA methylation and opposite to that of the TET protein levels during female germ cell and preimplantation embryo development. Our findings provide insight into the complex molecular mechanisms that regulate human embryo development, and a foundation for further elucidation of early embryonic development and informed reproductive medicine.

show abstract

DNA hypomethylation upregulates expression of the MGAT3 gene in HepG2 cells and leads to changes in N-glycosylation of secreted glycoproteins

Cited by 25 publications

References 51 publications

Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan*[S]

Bisecting GlcNAc Is a General Suppressor of Terminal Modification of N-glycan*[S]

Alterations in the glycome after HDAC inhibition impact oncogenic potential in epigenetically plastic SW13 cells

Integrated Glycosylation Patterns of Glycoproteins and DNA Methylation Landscapes in Mammalian Oogenesis and Preimplantation Embryo Development

Contact Info

Product

Resources

About