GnT-V expression and metastatic phenotypes in macrophage–melanoma fusion hybrids is down-regulated by 5-Aza-dC: Evidence for methylation sensitive, extragenic regulation of GnT-V transcription

Chakraborty, Ashok; Sousa, Josane de Frietas; Chakraborty, Debjit; Funasaka, Yoko; Bhattacharya, Malay; Chatterjee, Amitava; Pawelek, John M.

doi:10.1016/j.gene.2006.01.031

Cited by 24 publications

(20 citation statements)

References 23 publications

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“…Chakraborty et al demonstrated that MGAT5 was downregulated by 5-AZA-dC treatment in macrophage-melanoma hybrid cells. 35 They further demonstrated that MGAT5 was not directly controlled by methylation in these hybrid cells, but by the transcriptional repressor Nm23, which was itself regulated by hypermethylation. The discrepancies in the effect 5-AZA-dC has on the expression of MGAT5 are likely to be due to the different cells used in the two studies.…”

Section: Discussionmentioning

confidence: 95%

5-AZA-2'-deoxycytidine induced demethylation influencesN-glycosylation of secreted glycoproteins in ovarian cancer

Saldova

Dempsey²,

Pérez-Garay³

et al. 2011

Epigenetics

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Glycosylation is the most common posttranslational modification of proteins and is highly reflective of changes in the environment of a cell. Epigenetic modifications to the genome are stably transmitted to daughter cells without the requirement for genetic sequence alterations. Aberrant regulation of both epigenetic programming and glycosylation patterning are integral aspects of carcinogenesis. The objective of this study was to determine the interplay between these two complex cellular processes. We demonstrate that global DNA methylation changes in ovarian cancer epithelial cells (OVCAR3) resulted in significant alterations in the glycosylation of secreted glycoproteins. These changes included a reduction in core fucosylation, increased branching and increased sialylation. We further show that the change in core fucose levels was mirrored by altered expression of GMDS and FX, key enzymes in fucose biosynthesis. Alterations in the expression of key glycosyltransferase enzymes such as MGAT5 reflect the changes seen in the branching and sialylation of secreted glycans. Overall, our results highlight that modifications to the epigenetic machinery have a profound effect on the glycan structures generated by cells, which may be a key step in understanding metastasis and drug resistance during cancer progression.

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Section: Discussionmentioning

confidence: 95%

5-AZA-2'-deoxycytidine induced demethylation influencesN-glycosylation of secreted glycoproteins in ovarian cancer

Saldova

Dempsey²,

Pérez-Garay³

et al. 2011

Epigenetics

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“…For example, we previously showed that the synthesis of MUC1-associated sLex in HCT15 colon cancer cells was controlled by methylation of the ST3GAL6 promoter [19]. The expression of many other glycosyltransferase genes is also under the control of DNA methylation [26], [35], [36], [37], [38], [39]. Apart from glycosyltransferases, many other glycogenes, including enzymes involved in the biosynthesis of sugar nucleotides [40], [41], galectins [42], and some transporters [27], also are regulated by epigenetics.…”

Section: Discussionmentioning

confidence: 99%

Prostatic Cell-Specific Regulation of the Synthesis of MUC1-Associated Sialyl Lewis a

2013

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Sialyl Lewis antigens are selectin ligands involved in leukocyte trafficking and cancer metastasis. Biosynthesis of these selectin ligands occurs by the sequential actions of several glycosyltransferases in the Golgi apparatus following synthesis of the protein backbone in the endoplasmic reticulum. In this study, we examine how the synthesis of sialyl Lewis a (sLea) is regulated in prostatic cells and identify a mucin that carries this glycotope. We treat human prostatic cells including one normal and three cancerous cells with histone deacetylase inhibitors, valproic acid, tricostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA), and then monitor the expression of sLea. We have found that SAHA enhances the production of sLea in normal prostatic RWPE-1 cells but not prostatic cancer cells. Employing siRNA technology and co-immunoprecipitation, we show that the sLea is associated with MUC1, which is confirmed by confocal immunofluorescence microscopy and proximity ligation assay. The SAHA-induced production of sLea in RWPE-1 cells is resulted from upregulation of B3GALT1 gene via enhancement of acetylated histone-3 and histone-4. Interestingly, PC3 and LNCaP C-81 cells do not produce detectable amounts of sLea despite expressing high levels of B3GALT1. However, the MUC1-associated sLea is generated in these cells after introduction of MUC1 cDNA. We conclude that the synthesis of sLea is controlled by not only peptide backbone of the glycoprotein but also glycoprotein-specific glycosyltransferases involved in the synthesis of sLea. Further, the SAHA induction of this selectin ligand in normal prostatic cells may pose a potentially serious side effect of this drug recently approved by the US Food and Drug Administration.

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“…Expression of the ETS-like transcription factor Elk-1 gene is regulated by TATA box and the Erg-1 binding site, which functions specifically in monocytes [24]. Many glycosyltransferase genes have been reported to be regulated by Est family transcription factors, including GlcNAcT V [25–30], FUT4 [31], GalT I [32], GalT V [33], ST3Gal IV [34], and ST6GalNAc I [35]. …”

Section: Resultsmentioning

confidence: 99%

Transcriptional Regulation of Fucosyltransferase 1 Gene Expression in Colon Cancer Cells

Taniuchi

Higai

Tanaka

et al. 2013

The Scientific World Journal

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The α1,2-fucosyltransferase I (FUT1) enzyme is important for the biosynthesis of H antigens, Lewis B, and Lewis Y. In this study, we clarified the transcriptional regulation of FUT1 in the DLD-1 colon cancer cell line, which has high expression of Lewis B and Lewis Y antigens, expresses the FUT1 gene, and shows α1,2-fucosyltransferase (FUT) activity. 5′-rapid amplification of cDNA ends revealed a FUT1 transcriptional start site −10 nucleotides upstream of the site registered at NM_000148 in the DataBase of Human Transcription Start Sites (DBTSS). Using the dual luciferase assay, FUT1 gene expression was shown to be regulated at the region −91 to −81 nt to the transcriptional start site, which contains the Elk-1 binding site. Site-directed mutagenesis of this region revealed the Elk-1 binding site to be essential for FUT1 transcription. Furthermore, transfection of the dominant negative Elk-1 gene, and the chromatin immunoprecipitation (CHIp) assay, supported Elk-1-dependent transcriptional regulation of FUT1 gene expression in DLD-1 cells. These results suggest that a defined region in the 5′-flanking region of FUT1 is critical for FUT1 transcription and that constitutive gene expression of FUT1 is regulated by Elk-1 in DLD-1 cells.

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GnT-V expression and metastatic phenotypes in macrophage–melanoma fusion hybrids is down-regulated by 5-Aza-dC: Evidence for methylation sensitive, extragenic regulation of GnT-V transcription

Cited by 24 publications

References 23 publications

5-AZA-2'-deoxycytidine induced demethylation influencesN-glycosylation of secreted glycoproteins in ovarian cancer

5-AZA-2'-deoxycytidine induced demethylation influencesN-glycosylation of secreted glycoproteins in ovarian cancer

Prostatic Cell-Specific Regulation of the Synthesis of MUC1-Associated Sialyl Lewis a

Transcriptional Regulation of Fucosyltransferase 1 Gene Expression in Colon Cancer Cells

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