Eicosapentaenoic acid induces DNA demethylation in carcinoma cells through a TET1-dependent mechanism

What is it about?

DNA methylation is characterized by genomic hypomethylation and regional hypermethylation in most cancer cells. Global hypomethylation may activate oncogenes and chromosomal instability while regional hypermethylation is one of the major mechanisms for silencing tumor-related genes. Demethylating agents can promote re-expression of tumor suppressor genes. Previously we found that EPA, an n-3 polyunsaturated fatty acid (PUFA), acted as a DNA demethylating agent in leukemia cells. In the present study we explored in solid cancer cells the molecular mechanism underlying EPA-related DNA demethylation. We found that EPA induces p21 expression thus inhibiting cancer cell cycle progression. In particular, EPA binds to both PPARgamma and RXRalpha receptors, which assemble the TET1-PPARgamma-RXRalpha protein complex that binds to a hypermethylated region on the p21 gene. TET1 demethylates this region by converting 5 methylcytosine to 5 hydroxymethylcytosine, thus exerting its anti-tumoral function. Our data represent the starting point for potential use of EPA in clinical trials. Interestingly, they pave the way for studying PUFAs-action as DNA demethylatiing agents in cancer and other diseases in which aberrant DNA methylation occurs.

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