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

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Veronica CeccarelliAlba Vecchini

Abstract

In cancer cells, global genomic hypomethylation is found together with localized hypermethylation of CpG islands within the promoters and regulatory regions of silenced tumor suppressor genes. Demethylating agents may reverse hypermethylation, thus promoting gene re-expression. Unfortunately, demethylating strategies are not efficient in solid tumor cells. DNA demethylation is mediated by ten-eleven translocation enzymes (TETs). They sequentially convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is associated with active transcription; 5-formylcytosine; and finally, 5-carboxylcytosine. Although α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid, the major n-3 polyunsaturated fatty acids, have anti-cancer effects, their action, as DNA-demethylating agents, has never been investigated in solid tumor cells. Here, we report that EPA demethylates DNA in hepatocarcinoma cells. EPA rapidly increases 5hmC on DNA, inducing p21Waf1/Cip1 gene expression, which slows cancer cell-cycle progression. We show that the underlying molecular mechanism involves TET1. EPA simultaneously binds peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα), thus promoting their heterod...Continue Reading

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Citations

Apr 17, 2019·Bioscience Reports·Songsong TengChengqing Yi
Jan 9, 2020·World Journal of Clinical Cases·Mostafa Moradi SarabiEbrahim Eftekhar
May 29, 2020·Prostaglandins, Leukotrienes, and Essential Fatty Acids·J Eduardo Pérez-MojicaGraham C Burdge
Jul 27, 2021·Environmental Science and Pollution Research International·Nasreddine El OmariAbdelhakim Bouyahya
Aug 24, 2021·Frontiers in Nutrition·Maja MiloševićVesna Vučić

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