Cancer is characterized by global epigenetic changes.One hallmark of, which received limited attention is the global loss of DNA methylation.We will present evidence that DNA demethylation leads to activation of genes,which promote the metastatic process.Examples are uPA, MMP2 MertK and different cytokines and bone degrading enzymes.If demethylation is driving cancer metastasis then blocking DNA demethylation should be able to reverse metastasis.We will des genes and cribe two strategies to do so.First, we showed that the natural methyl donor Sadenosylmethionine inhibits active DNA demethylation and thus it blocks the demethylation of pro-metastatic genes.We show that in vitro SAM treatment silences metastatic genes and blocks metastasis in vitro and in vivo.Second,we show that the methylated DNA binding protein MBD2 is involved in demethylation and activation of prometastatic genes in cancer.We demonstrate using a combination of gain of function and loss of function approaches that MBD2 plays a critical role in triggering and maintaining the metastatic state and that MBD2 resides downstream to the RAS signaling pathway.Inhibition of MBD2 is proposed as a new therapeutic strategy to metastatic cancer.We developed antisense inhibitors of MBD2 which are highly effective against several human xenoplants in nude mice in vivo.Supported by a grant from the National Cancer Institute of Canada to MS.