OK this one is a week old, but we love a paper that addresses epigenetic regulation of epigenetic regulators, so we couldn’t resist a recent PNAS report that identified a miRNA DNA methylation signature for human cancer metastasis. Like proteins, miRNAs act as oncogenes, tumor suppressors, and metastatic mediators, and their expression can be influenced by promoter methylation status. So Manel Esteller at the Spanish National Cancer Research Center and colleagues at several universities, hospitals, and institutes in the U.S. and Europe characterized miRNAs that were upregulated upon treatment of metastatic cancer cells with a demethylating agent.
Among the miRNAs that were activated by the demethylating drug, miR-148a, miR-34b/c, and miR-9 were specifically hypermethylated and silenced in cancer cells compared with normal tissues. Interestingly, when miR-148a or miR-34b/c was re-introduced to cancer cells in which the gene was silenced by hypermethylation, the cells showed impaired motility and reduced tumor growth and metastasis in xenograft models. Expression of these tumor suppressor miRNAs down-regulated their oncogenic target proteins, such as C-MYC and CDK6. Furthermore, hypermethylation of miR-148a, miR-34b/c, and miR-9 was associated with lymph node metastasis of human primary malignancies. These results indicate that DNA-methylation-induced silencing of tumor suppressor miRNAs contributes to human cancer metastasis. Check out the details at: PNAS, September 2008