The role of DNA hypomethylation in the control of stromelysin gene expression.

Genome-wide DNA hypomethylation is a critical mechanism underlying neoplastic transformation. Thus, genes that are suppressed in normal tissues or in specific cell types may become aberrantly expressed in neoplasia. To determine whether DNA methylation can modulate matrix metalloproteinase (mmp) gene expression, we have used a genetically engineered cell line in which both key DNA methyltransferase genes, Dnmt-1 and Dnmt-3b, were removed by homologous recombination. We found that cells bearing a dual knock-out of both Dnmt-1 and Dnmt-3b genes induced de novo expression of mmp-3 gene, but not that of mmp-1 and mmp-2. Furthermore, treatment of the wild-type cells with DNA methylase inhibitors 5-aza-dC and zebularine also induced mmp-3 gene expression. On the other hand, in vitro methylation of the mmp-3 promoter suppressed its transcriptional activity. Finally, we found that induction of mmp-3 and mmp-10 gene expression by hypomethylation was cell-specific, suggesting that epigenetic changes may predispose cells to express stromelysin genes.