We show for the first time that
DNA isolated from human colon
carcinoma tissue exhibits a selective hypomethylation of
versican gene, which encodes a large
chondroitin sulfate proteoglycan. The degree of methylation of CpG sequences of
versican gene locus, as determined by isoschizomeric
endonucleases and Southern hybridization, is about three times lower than that found in either normal colon or
ulcerative colitis tissues. Hypomethylation can be observed in both benign and malignant
colonic neoplasms; however, there is no correlation with increased expression since
versican mRNA levels do not significantly vary between normal and neoplastic tissues. We further show that
versican gene locus from malignant tissue, but not from normal or
ulcerative colitis tissues, contains Hind III hypersensitive sites which also comprise hypomethylated CpG sequences. Analysis of
versican methylation status in colon
carcinoma cells and benign mesenchymal cells derived from human colon suggests that the changes observed in vivo derive from demethylating events involving host stromal cells rather than
tumor cells themselves. These findings demonstrate that changes in
versican gene methylation are specific for
colonic neoplasms, that these changes may precede malignant transformation, and that
inflammation and tissue remodelling alone are not enough to generate these changes in
proteoglycan gene methylation and nuclease
hypersensitivity.