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.
Highlights
Heparan sulfate proteoglycans (HSPGs) are ubiquitous cell surface molecules that consist of a protein core with attached heparan sulfate (HS) glycosaminoglycan chains
We have chosen to analyze the effect of changes in HS fine structure via 2OST siRNA on prostate cancer cell proliferation and invasion to ask how changes in heparan sulfation may arise during cancer progression (Figure 8)
Our studies have demonstrated that 2OST is required for maximal proliferation and invasion of cells in the LNCaPC4-2B model
Summary
Heparan sulfate proteoglycans (HSPGs) are ubiquitous cell surface molecules that consist of a protein core with attached heparan sulfate (HS) glycosaminoglycan chains. In the LNCaP-C4-2B cell line series, a well-known model of prostate cancer progression [10,11,12], we have shown that SHH signaling increases with increasing metastatic potential but Pln protein levels do not [8] Instead, in this cell line series, Pln isolated from more highly metastatic cell lines binds more SHH than an equal amount of Pln from more benign cell lines. In this cell line series, Pln isolated from more highly metastatic cell lines binds more SHH than an equal amount of Pln from more benign cell lines This data suggested an alternative mechanism, whereby during prostate cancer progression, cells produce a different, more efficient isoform of Pln protein to increase SHH signaling rather than expressing more of the same isoform as before. Given the bipartite structure of HSPGs and the known contribution of their sugar chains to the regulation of growth factor signaling, differential structure of the sugar chains is an obvious possibility in the generation of different Pln isoforms
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