The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer Mao, X.; Gauche, C.; Coughtrie, M. W. H.; Bui, C.; Gulberti, S.; Merhi-Soussi, F. Citation for published version (APA):Mao, X., Gauche, C., Coughtrie, M. W. H., Bui, C., Gulberti, S., Merhi-Soussi, F., ... Fournel-Gigleux, S. (2016). The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer. Oncogene, 35, 5043-5055. DOI: 10.1038/onc.2016 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3--O--sulfotransferase 3--OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3--OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in HER2--positive (HER2+) SKBR3 cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3--OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3--OST3A exerted dual activities acting as tumor--suppressor in lumA--MCF--7 and triple negative--MDA--MB--231 cells, or as an oncogenic factor in HER2+--SKBR3 cells. Mechanistically, fluorescence--resonance energy transfer (FRET)--fluorescence--lifetime imaging microscopy (FLIM) experiments indicated that the effects of 3--OST3A in MCF--7 cells were mediated by altered interactions between HS and fibroblast growth factor--7 (FGF--7). Further, this interplay between HS and FGF--7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3--O--sulfation affects FGFR...
Background: Glycosyltransferase inhibitors have important applications in therapeutics and as chemical biology tools.Results: The human β1,4-galactosyltransferase 7 enzyme active site was mapped by modeling, mutagenesis, and in vitro/in cellulo assays, and novel inhibitors were synthesized.Conclusion: An efficient inhibitor of β1,4-galactosyltransferase 7 and glycosaminoglycan synthesis was obtained.Significance: This inhibitory molecule can be exploited to investigate glycosaminoglycan biology and modulate glycosaminoglycan synthesis in therapeutics.
Different mono-xylosides and their corresponding xylobiosides obtained by a chemo-enzymatic approach featuring various substituents attached to a triazole ring were probed as priming agents for glycosaminoglycan (GAG) biosynthesis in the xylosyltransferase-deficient pgsA-745 Chinese hamster ovary cell line. Xylosides containing a hydrophobic aglycone moiety were the most efficient priming agents. Mono-xylosides induced higher GAG biosynthesis in comparison with their corresponding xylobiosides. The influence of the degree of polymerization of the carbohydrate part on the priming activity was investigated through different experiments. We demonstrated that in case of mono-xylosides, the cellular uptake as well as the affinity and the catalytic efficiency of β-1,4-galactosyltransferase 7 were higher than for xylobiosides. Altogether, these results indicate that hydrophobicity of the aglycone and degree of polymerization of glycone moiety were critical factors for an optimal priming activity for GAG biosynthesis.
Proteoglycans (PGs) are complex macromolecules that are composed of glycosaminoglycan (GAG) chains covalently attached to a core protein through a tetrasaccharide linker. The biosynthesis of PGs is complex and involves a large number of glycosyltranferases. Here we present a structure-activity study of human β4GalT7, which transfers the first Gal residue onto a xyloside moiety of the linkage region. An efficient and regiocontrolled synthesis of a library of modified analogs of 4-methylumbelliferyl xyloside (XylMU) is reported herein. Hydroxyl groups at the position C-2, C-3 or C-4 have been epimerized and/or replaced by a hydrogen or a fluorine, while the anomeric oxygen was replaced by either a sulfur or a sulfone. The effect of these compounds on human β4GalT7 activity in vitro and on GAG biosynthesis in cellulo was then evaluated.
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