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.

Keywords: cancer; epigenetic regulation; heparan sulfate; immune escape; sulfotransferase.

Figure 1

Schematic representation of HS modifications. The HS polysaccharide is linked by the tetrasaccharide linker [Xyl-Gal-Gal-GlcUA] to a specific serine residue within the HSPG core protein. Elongation of the chain is achieved through the alternative addition of GlcUA and GlcNac residues by the polymerases EXT1/EXT2. (A) The disaccharide units [GlcUA-GlcNAc] are modified by the actions of sulfotransferases and epimerase. The sites of modification by N-deacetylases/N-sulfotransferases (NDST), C5-epimerase, HS 2-O-sulfotransferase (HS2ST), HS 6-O-sulfotransferases (HS6STs), and HS 3-O-sulfotransferases (HS3STs) are indicated. (B) HS modifications do not go to completion, resulting in domains with high, intermediate, and low levels of sulfation, enabling the generation of many HS structures and potential ligand-binding sites. NS, N-sulfo group on GlcN residue; 2S, 2-O-sulfo group on uronic acid residue; 3S and 6S, 3-O and 6-O-sulfo groups on GlcN residue.