Epigenetic Regulation of the Biosynthesis & Enzymatic Modification of Heparan Sulfate Proteoglycans: Implications for Tumorigenesis and Cancer Biomarkers

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.

Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation

“…Since the biosynthesis of HS is performed in a non-template manner by a complex system of biosynthetic enzymes, disturbances in its work may be the most likely cause of changes in the structure and/or composition of HS in tumours [ 17 , 18 ]. The transcriptional activity of this system is tissue-specific [ 19 ], and it is under control of complex epigenetic mechanisms [ 20 ]. There have been practically no comprehensive studies of the HS biosynthetic system in gliomas, and the only known analysis of the expression pattern of HS biosynthesis-related genes in glioblastoma was carried out by Wade et al, 2013, using data from the Cancer Genome Atlas (available online: ) [ 21 ].…”

The Challenge of Modulating Heparan Sulfate Turnover by Multitarget Heparin Derivatives

“…Therefore, alteration of the normal expression levels of HSPGs has often been described in tumors. Several HSPGs have been shown to be upregulated in many cancers [114]; for example, increasing expression level of Agrin in hepatocellular carcinoma [115] and of glypican-1 in pancreas carcinoma was detected and associated with poor prognosis [116]. Levels of glypican-1 and syndecan-2 are also increased in colorectal cancer [117].…”

“…In general, remodeling of HSPGs through enzymatic modification of HS chains is associated with malignant transformation of cells and can potentially serve as molecular biomarker to aid in the diagnosis and prognosis of cancer [114,126]. Also, alteration of glycosylation affects cellular adhesion and is associated with oncogenic transformation and metastasis [114]. Indeed, altered HSPGs glycosylation has been described in lung and brain cancer [127].…”

Synergistic Effect of Network-Based Multicomponent Drugs: An Investigation on the Treatment of Non-Small-Cell Lung Cancer with Compound Liuju Formula

“…Meanwhile, the activation of TNF signaling by inflammatory signaling plays an important role in the development of tumors [45]. Also, heparin sulfate proteoglycans (HSPGs) in the proteoglycans in cancer pathway are key components of the extracellular matrix that mediate cell Evidence-Based Complementary and Alternative Medicine Evidence-Based Complementary and Alternative Medicine 7 proliferation, invasion, and cell signaling [46,47]. erefore, tumor invasion is an important process of tumor growth and metastasis.…”