Role of Heparan Sulfate 2-O-Sulfotransferase in Prostate Cancer Cell Proliferation, Invasion, and Growth Factor Signaling

Abstract

Heparan-sulfate proteoglycans (HSPGs) are required for maximal growth factor signaling in prostate cancer progression. The degree of sulfate modification on the covalently attached heparan sulfate (HS) chains is one of the determining factors of growth factor-HSPG interactions. Sulfate groups are transferred to HS chains via a series of O-sulfotransferases. In the present study, we demonstrate that Heparan sulfate 2-O-sulfotransferase (2OST) is essential for maximal proliferation and invasion of prostate cancer cells in the LNCaP-C4-2B model. We also show that a decrease in invasion due to 2OST siRNA is associated with an increase in actin and E-cadherin accumulation at the cell surface. 2OST expression correlates with increasing metastatic potential in this model. We demonstrate that 2OST expression is upregulated by the stress-inducible transcription factors HIF1α, ATF2, and NFκB. Chromatin immunoprecipitation analysis suggests that HIF1α and ATF2 act directly on the 2OST promoter, while NFκB acts indirectly.

Induction of reactive oxygen species generation inhibits epithelial–mesenchymal transition and promotes growth arrest in prostate cancer cells

“…When CaP cells were treated with pso, invasion by CaP cells was significantly inhibited (Figure 5B). We observed PC-3 cells potently invaded through matrigel when compared to C4-2B cells and the results are consistent with published data [30][31][32][33]. Furthermore, we confirmed that pso treatment decreased the expression of slug, vimentin, and bcatenin in PC-3 cells by Western blot analysis (Figure 5C).…”

Heparan sulfate signaling in cancer

“…Expression of HS3ST2 is epigenetically silenced in lung cancers, where it functions to suppress tumor growth and invasion [80]. By contrast, HS2ST1, HS3ST3B1, HS3ST4, and HS6ST1 and 2 promote cell proliferation, invasiveness and tumor angiogenesis [77, 81-83], presumably via increased HS sulfation and enhanced growth factor signaling.…”

Alterations of Heparan Sulfate Proteoglycans in Cancer

“…The O-sulphotransferases (HSSTs) group comprises the largest cluster of genes encoding the HS biosynthetic machinery and whose expression is most often deregulated in various tumors, many interesting examples of which have been described. Concerning HS2ST1, studies have demonstrated that it is crucial for cell proliferation and invasion, and its expression correlates with increasing metastatic capacity, especially in prostate cancer [13]. Additionally, overexpression of HS6ST1 in ovarian cancer and HCC, and overexpression of HS6ST2 in colorectal cancer and ovarian cancer has been described [14].…”