Hypoxia negatively regulates heparan sulfatase 2 expression in renal cancer cell lines.

Inactivation of von Hippel-Lindau (VHL), a tumor suppressor gene is often associated with clear cell renal cell carcinoma (ccRCC). VHL inactivation leads to multitude of responses including enhanced growth factor signaling such as bFGF2, SDF-1α, and HGF. Here, we have identified a novel VHL-inducible gene, heparan sulfatase 2 (HSulf-2) that attenuates heparan-binding growth factor such as bFGF2 signaling. VHL-mediated HIF-1 alpha degradation was essential to restore HSulf-2 expression. Mechanistically, HSulf-2 negatively regulated vimentin expression and knockdown of vimentin abolished cell migration. This study reveals a novel layer of regulation of heparan-binding growth factor signaling via modulation of heparan sulfate by HSulf-2 in ccRCC.