Abstract
Heparan Sulfate Proteoglycans (HSPGs) are important cell surface and Extracellular Matrix (ECM) maestros involved in the orchestration of multiple cellular events in physiology and pathology. These glycoconjugates bind to various bioactive proteins via their Heparan Sulfate (HS) chains, but also through the protein backbone, and function as scaffolds for protein-protein interactions, modulating extracellular ligand gradients, cell signalling networks and cell-cell/cell-ECM interactions. The structural features of HS chains, including length and sulfation patterns, are crucial for the biological roles displayed by HSPGs, as these features determine HS chains binding affinities and selectivity. The large HS structural diversity results from a tightly controlled biosynthetic pathway that is differently regulated in different organs, stages of development and pathologies, including cancer. This review addresses the regulatory mechanisms underlying HS biosynthesis, with a particular focus on the catalytic activity of the enzymes responsible for HS glycan sequences and sulfation motifs, namely D-Glucuronyl C5-Epimerase, N- and O-Sulfotransferases. Moreover, we provide insights on the impact of different HS structural epitopes over HSPG-protein interactions and cell signalling, as well as on the effects of deregulated expression of HS modifying enzymes in the development and progression of cancer. Finally, we discuss the clinical potential of HS biosynthetic enzymes as novel targets for therapy, and highlight the importance of developing new HS-based tools for better patients’ stratification and cancer treatment.
Highlights
Heparan Sulfate Proteoglycans (HSPGs) are important glycoconjugates ubiquitously expressed on cells glycocalyx and Extracellular Matrix (ECM), as well as in secreted extracellular vesicles [1,2,3]
The biosynthesis of HS chains occurs at the endoplasmic reticulumGolgi apparatus interface and in the Golgi apparatus, and includes: i) assembly of a GAG-protein linker, which initiates the covalent binding of HS to proteoglycan core proteins; ii) the polymerization of the HS chain; and iii) the structural modification of the elongated chain [8]
The increasing need for efficient and highly specific biomarkers, and personalized anti-cancer therapies, including new selective drugs, prompts a more in-depth research of these promising tools, inciting further investigation of HS fine structures and their impact in cancer cell behaviour. Many studies in this field, that have been performed to infer about structural-functional relationships, resorted to artificial in vitro models, via binding assays and using heavily sulfated heparin molecules and short HS-like oligosaccharides, with the purpose of unravelling bioactive sulfation arrangements and distinctive protein-binding sites within HS chains [70, 148, 149]
Summary
Heparan Sulfate Proteoglycans (HSPGs) are important glycoconjugates ubiquitously expressed on cells glycocalyx and Extracellular Matrix (ECM), as well as in secreted extracellular vesicles [1,2,3]. M. et al studied the impact of another NDST isoform, NDST1, on tumour angiogenesis, and showed that endothelial cells isolated from Ndst1 KO mice synthesized structurally modified HS chains that impaired angiogenesis-related signalling pathways, leading to decreased vascularization of lung tumours and consequent reduced tumour growth [96].
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