Heparanase-enhanced Shedding of Syndecan-1 and Its Role in Driving Disease Pathogenesis and Progression

Abstract

<jats:p> Both heparanase and syndecan-1 are known to be present and active in disease pathobiology. An important feature of syndecan-1 related to its role in pathologies is that it can be shed from the surface of cells as an intact ectodomain composed of the extracellular core protein and attached heparan sulfate and chondroitin sulfate chains. Shed syndecan-1 remains functional and impacts cell behavior both locally and distally from its cell of origin. Shedding of syndecan-1 is initiated by a variety of stimuli and accomplished predominantly by the action of matrix metalloproteinases. The accessibility of these proteases to the core protein of syndecan-1 is enhanced, and shedding facilitated, when the heparan sulfate chains of syndecan-1 have been shortened by the enzymatic activity of heparanase. Interestingly, heparanase also enhances shedding by upregulating the expression of matrix metalloproteinases. Recent studies have revealed that heparanase-induced syndecan-1 shedding contributes to the pathogenesis and progression of cancer and viral infection, as well as other septic and non-septic inflammatory states. This review discusses the heparanase/shed syndecan-1 axis in disease pathogenesis and progression, the potential of targeting this axis therapeutically, and the possibility that this axis is widespread and of influence in many diseases. </jats:p>

The Heparan Sulfate Sulfotransferases HS2ST1 and HS3ST2 Are Novel Regulators of Breast Cancer Stem-Cell Properties

“…However, more complex regulatory mechanisms may occur at the level of cell surface availability of signaling receptors and co-receptors. For example, both the shedding of Sdc-1 and activation of notch can be mediated by gamma-secretase ( Pasqualon et al, 2015 ), and Sdc-1 shedding is regulated by HPSE ( Rangarajan et al, 2020 ), which is expressed in a HS-sulfotransferase-dependent manner according to our study. Finally, HS2ST1-modified Sdc-1 was shown to prevent cellular senescence through the regulation of FGFR1 endocytosis ( Kang et al, 2020 ), and similar mechanisms could play a role in the HS2ST1-dependent CSC phenotype.…”

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

“…Heparanase is an endoglucuronidase that specifically cleaves HS chains, acting on the GlcA–GlcNS glycosidic bond [ 4 , 6 ]. As a result of the heparanase activity, shorter HS fragments are released that may either promote ECM remodeling or activate HSPG catabolism [ 4 , 7 ]. Extracellular endosulfatases (SULF1/2) promote 6- O -desulfation of HS, starting from the non-reducing end of HS chain S-domains, with a strong preference for the [Glc/IdoA(2S)-GlcNS(6S)] trisulfated disaccharides, which are mostly present within HS functional S-domains [ 4 , 8 ].…”

“…Beyond the evidence that viruses use HSPGs for attachment and entry into host cells, either HSPG biosynthetic or post-synthetic modifying enzymes have emerged as critical players in the viral invasion of target cells at various steps of their life cycles [ 4 , 7 , 99 ]. Table 2 reports a list of the viruses whose ability to enter and to infect host organisms is regulated by the differential activity of HSPG biosynthetic and/or modifying enzymes [ 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ].…”

Syndecan-1 (CD138), Carcinomas and EMT

“…Heparanase selectively cleaves HS chains, liberating oligosaccharides that may be biologically active [76]. In addition, removal of HS by the enzyme exposes the syndecan core protein, which becomes even more sensitive to protease cleavage [77].…”