The Emerging Roles of Heparan Sulfate 3-O-Sulfotransferases in Cancer

Abstract

Alteration in the expression of heparan sulfate (HS)-modifying enzymes has been frequently observed in cancer. Consequently, dysregulation of the HS biosynthetic machinery results in dramatic changes in the HS structure, thereby impacting a range of pivotal cellular processes involved in tumorigenesis and cancer progression including proliferation, migration, apoptosis, and immune escape. HS 3- O -sulfotransferases (HS3STs) catalyse the maturation step of glucosaminyl 3- O -sulfation within HS chains. Although seven HS3ST isozymes have been described in human, 3- O -sulfation is a rare modification and only a few biological processes have been described to be influenced by 3- O -sulfated HS. An aberrant expression of HS3STs has been reported in a variety of cancers. Thus, it was suggested that changes in the expression of these enzymes as a result of tumorigenesis or tumor growth may critically influence cancer cell behavior. In accordance with this assumption, a number of studies have documented the epigenetic repression of HS3ST2 and HS3ST3A in many cancers. However, the situation is not so clear, and there is accumulating evidence that HS3ST2, HS3ST3A, HS3ST3B, and HS3ST4 may also act as tumor-promoting enzymes in a number of cancer cells depending on their phenotypes and molecular signatures. In this mini-review, we focus on the recent insights regarding the abnormal expression of HS3STs in cancer and discuss the functional consequences on tumor cell behavior. In term of clinical outcome, further investigations are needed to explore the potential value of HS3STs and/or their 3- O -sulfated products as targets for therapeutic strategies in cancer treatment.

In-Depth Analysis of Genetic Variation Associated with Severe West Nile Viral Disease

“…When we analyzed gene-gene interactions, many of the top pairs included an intergenic region, highlighting the importance of ongoing efforts to understand the roles and effects of these areas. The top interaction involved a SNP in the HS3ST4 gene, which encodes the enzyme heparan sulfate D -glucosaminyl 3- O -sulfotransferase 4 and has been linked to herpes simplex virus type 1 pathogenesis and tumor growth [ 55 , 56 ]. HS3ST4 has been shown to be regulated by TRF2, with abnormal expression limiting natural killer cell recruitment and activation; notably, natural killer cells play an important role in the immune system response to WNV infection [ 57 , 58 , 59 ].…”

Heparan Sulfate Proteoglycans Biosynthesis and Post Synthesis Mechanisms Combine Few Enzymes and Few Core Proteins to Generate Extensive Structural and Functional Diversity

“…The catalytic mechanism of 3-OST3 has also been studied using computational methods, which suggest how the protonation/deprotonation states of the catalytic residues (His186, Glu184 and Asp189) catalyse the transfer of sulfo groups from PAPS co-substrate to HS glucosamine units [ 203 ]. The expression of 3-OST genes appears to be tightly controlled in a spatiotemporal manner [ 204 ]. However, with very few exceptions, every cell line expresses at least one and generally more than one 3-OST.…”

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

“…Heparan sulfate (HS) is a highly sulfated glycosaminoglycan (GAG) found on the cell surface and in the extracellular matrix (ECM) (Zhang, 2010;Karamanos et al, 2018). Its localization is determined by the core protein, while the HS chains determine the affinity to numerous ligands such as growth factors, cytokines, proteases, lipoproteins and ECM components (Denys and Allain, 2019). HS mediates cell-cell and cell-ECM communication, leading to different pathological and physiological effects, including embryonic development, cell growth and differentiation, homeostasis, inflammatory responses, tumor growth and microbial infection (Li and Kusche-Gullberg, 2016).…”

“…While 2-O sulfation occurs at the uronic acids (mainly IdoA), 6-O and 3-O sulfation occur at the GlcN residues (Zhang, 2010). Aberrant regulation of sulfotransferase expression affects several processes regulated by HS, ranging from organ development to inflammation (Merry and Wilson, 2002;Denys and Allain, 2019).…”

“…Notably, HS3ST is misexpressed in different types of cancers. However, its effect on cancer is still not clear, as some reports show antitumoral effects and others describe tumor-promoting activities (Vijaya Kumar et al, 2014;Denys and Allain, 2019).…”