The heparan sulfate 3-O-sulfotransferases (HS3ST) 2, 3B and 4 enhance proliferation and survival in breast cancer MDA-MB-231 cells

• Published in: PloS one Vol. 13; no. 3; p. e0194676
• Main Authors: Hellec, Charles, Delos, Maxime, Carpentier, Mathieu, Denys, Agnès, Allain, Fabrice
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2018; Public Library of Science (PLoS)
• Subjects: AKT protein; Apoptosis; Apoptosis - genetics; Binding sites; Biochemistry, Molecular Biology; Biological activity; Biology and Life Sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell death; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cell survival; Cell Survival - genetics; Female; Gene Expression Regulation, Enzymologic - physiology; Gene Expression Regulation, Neoplastic; Heparan sulfate; Heparitin Sulfate - metabolism; Humans; Isoenzymes; Killer Cells, Natural - immunology; Kinases; Life Sciences; Ligands; Medicine and health sciences; NF-κB protein; Phenotypes; Physical Sciences; Physiology; Proteins; Research and Analysis Methods; Signal transduction; Signal Transduction - genetics; Src protein; Sulfates; Sulfation; Sulfotransferases - genetics; Sulfotransferases - metabolism; Sulfotransferases - physiology; Survivin; XIAP protein; France; United States > US; NK cells; disaccharides; transcription factors; isozymes; transfection; breast cancer; apoptosis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0194676

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.