Emerging data suggest that signaling by
heparin-binding
growth factors is influenced by the sulfation state of
N-acetylglucosamine residues of
heparan sulfate proteoglycans (HSPGs). Here we report that the recently identified
protein HSulf-1, a
heparin-degrading endosulfatase, encodes a cell surface-associated
enzyme that diminishes sulfation of cell surface HSPGs. The message encoding this
enzyme is readily detectable in a variety of normal tissues, including normal ovarian surface epithelial cells, but is undetectable in 5 of 7 ovarian
carcinoma cell lines and markedly diminished or undetectable in approximately 75% of
ovarian cancers. Similar down-regulation is also observed in breast, pancreatic, renal cells, and
hepatocellular carcinoma lines. Re-expression of HSulf-1 in
ovarian cancer cell lines resulted in diminished
HSPG sulfation, diminished phosphorylation of
receptor tyrosine kinases that require sulfated HSPGs as co-receptors for their cognate
ligands, and diminished downstream signaling through the
extracellular signal-regulated kinase pathway
after treatment with
fibroblast growth factor-2 or
heparin-binding
epidermal growth factor. Consistent with these changes, HSulf-1 re-expression resulted in reduced proliferation as well as sensitivity to induction of apoptosis by the broad spectrum
kinase inhibitor
staurosporine and the chemotherapeutic agent
cisplatin. Collectively, these observations provide evidence that HSulf-1 modulates signaling by
heparin-binding
growth factors, and HSulf-1 down-regulation represents a novel mechanism by which
cancer cells can enhance
growth factor signaling.