Abstract
Emerging evidence suggests that the enzymes in the biosynthetic pathway for the synthesis of heparan sulfate moieties of heparan sulfate proteoglycans (HSPGs) are epigenetically regulated at many levels. As the exact composition of the heparan sulfate portion of the resulting HSPG molecules is critical to the broad spectrum of biological processes involved in oncogenesis, the epigenetic regulation of heparan sulfate biosynthesis has far-reaching effects on many cellular activities related to cancer progression. Given the current focus on developing new anti-cancer therapeutics focused on epigenetic targets, it is important to understand the effects that these emerging therapeutics may have on the synthesis of HSPGs as alterations in HSPG composition may have profound and unanticipated effects. As an introduction, this review will briefly summarize the variety of important roles which HSPGs play in a wide-spectrum of cancer-related cellular and physiological functions and then describe the biosynthesis of the heparan sulfate chains of HSPGs, including how alterations observed in cancer cells serve as potential biomarkers. This review will then focus on detailing the multiple levels of epigenetic regulation of the enzymes in the heparan sulfate synthesis pathway with a particular focus on regulation by miRNA and effects of epigenetic therapies on HSPGs. We will also explore the use of lectins to detect differences in heparan sulfate composition and preview their potential diagnostic and prognostic use in the clinic.
Highlights
Most of these cases arise due to mutations in the exostosin (EXT) genes EXT1 and EXT2, encoding enzymes involved in biosynthesis of heparan sulfate [51], and further work demonstrated that these mutations interfere with proper glycosylation and function of Heparan Sulfate Proteoglycans (HSPGs) [52]
This proposed complex may include the family of exostosin enzymes as the length of the HS chain may be regulated by NDST, a proposed member of the GAGosome [108], and there is increasing experimental evidence to support such a complex [115,141,142]
Zhang et al have proposed that the enzymes involved in the modification of HS chains are tightly regulated to read and write a code involved to synthesize the appropriate HS [143]
Summary
Heparan sulfate proteoglycans (HSPGs) are a diverse group of glycoproteins composed of one or more chains of heparan sulfate (HS) covalently bound to a core protein through a tetrasaccharide bridge. More than 25 enzymes have been identified that are involved in HS synthesis and modification [3] Due to their sulfation, the HS chains are negatively charged and can bind to many different ligands at the cell surface, within the extracellular matrix, and within the plasma [4]. (1) plasma membrane-associated; (2) secreted into the extracellular matrix; and (3) within secretory vesicles (as reviewed in [1]). Glypicans contain a hydrophobic domain at the C-terminus, allowing for the attachment of the protein to the GPI anchor. The second category of HSPGs are those secreted into the extracellular matrix (ECM) These include perlecan, agrin, and collagen XVIII, which are all large, multidomain proteins (reviewed in [1,20,21]). Serglycin is primarily expressed in hematopoietic and endothelial cells and serves an important role in formation and retention of inflammatory mediators inside storage granules and secretory vesicles [1,22]
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