Abstract
Heparan sulfate 3-O-sulfotransferases (HS3STs) catalyze the final maturation step of heparan sulfates. Although seven HS3ST isozymes have been described in human, 3-O-sulfation is a relatively rare modification, and only a few biological processes have been described to be influenced by 3-O-sulfated motifs. A conflicting literature has recently reported that HS3ST2, 3A, 3B and 4 may exhibit either tumor-promoting or anti-oncogenic properties, depending on the model used and cancer cell phenotype. Hence, we decided to compare the consequences of the overexpression of each of these HS3STs in the same cellular model. We demonstrated that, unlike HS3ST3A, the other three isozymes enhanced the proliferation of breast cancer MDA-MB-231 and BT-20 cells. Moreover, the colony forming capacity of MDA-MB-231 cells was markedly increased by the expression of HS3ST2, 3B and 4. No notable difference was observed between the three isozymes, meaning that the modifications catalyzed by each HS3ST had the same functional impact on cell behavior. We then demonstrated that overexpression of HS3ST2, 3B and 4 was accompanied by increased activation of c-Src, Akt and NF-κB and up-regulation of the anti-apoptotic proteins survivin and XIAP. In line with these findings, we showed that HS3ST-transfected cells are more resistant to cell death induction by pro-apoptotic stimuli or NK cells. Altogether, our findings demonstrate that HS3ST2, 3B and 4 share the same pro-tumoral activity and support the idea that these HS3STs could compensate each other for loss of their expression depending on the molecular signature of cancer cells and/or changes in the tumor environment.
Highlights
Heparan sulfate (HS) is a highly sulfated glycosaminoglycan found at the cell surface and in the extracellular matrix
HS3ST3A was described as a tumor regulator in the development of breast cancer, with contrasting anti-oncogenic or tumor-promoting effects depending on the phenotype of cancer cells [22]. All these studies suggest that abnormal expression of certain gD-type Heparan sulfate 3-O-sulfotransferases (HS3STs) may have a functional impact on cancer cell behavior
When compared with parental cells, we found that the expression of each HS3ST enhanced the binding of HS4C3 antibody (Fig 1C), which preferentially reacts with highly sulfated HS epitopes containing 3-O-sulfate groups [23]
Summary
Heparan sulfate (HS) is a highly sulfated glycosaminoglycan found at the cell surface and in the extracellular matrix. It mediates cell-cell and cell-matrix communications and regulates the binding of a large number of ligands, resulting in a variety of physiological and pathological effects, such as in embryonic development, cell growth and differentiation, homeostasis, inflammatory response, tumor growth and microbial infection.
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