The
heparan sulfate 6-O-endosulfatase (SULF2) promotes growth and
metastasis of solid
tumors. We recently identified that
cytosine methylation of the SULF2 promoter is associated with better survival of resected
lung adenocarcinoma patients, and now also demonstrates a marginal improvement in survival of advanced
non-small cell lung cancer (NSCLC) patients receiving standard
chemotherapy (hazard ratio=0.63, P=0.07). Subsequent studies focused on investigating the effect of methylation on SULF2 expression and its genome-wide impact. The genes and pathways modulated by epigenetic inactivation of SULF2 and the effects on sensitivity to
chemotherapy were characterized in vitro and in vivo. Silencing SULF2 through
small interfering RNA or methylation primarily increased expression of
interferon-inducible genes including ISG15, a marker for increased sensitivity to topoisomerase-1 inhibitors such as
camptothecin (
CPT). NSCLC cell lines with methylated SULF2 (SULF2M) express 60-fold higher ISG15 compared with SULF2 unmethylated (SULF2U) NSCLC cell lines and normal human bronchial epithelial cells. In vitro, SULF2M and high ISG15 (ISG15H)-expressing NSCLC cell lines were 134-fold more sensitive to
CPT than SULF2U and low ISG15 (ISG15L)-expressing cell lines.
Topotecan, a soluble analog of
CPT and FDA-approved anticancer
drug, dramatically arrested the growth of SULF2M-ISG15H, but not SULF2U-ISG15L lung
tumors in nude mice (P<0.002). Similarly, high ISG15 expression that is comparable to the
topotecan (
TPT)-sensitive NSCLC cell lines was found in
tumors from 25% of NSCLC patients compared with normal lung, indicating a potential to identify and target the most sensitive NSCLC subpopulation for personalized
TPT therapy.