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It is widely accepted that aberrant DNA methylation at promoter regions commonly occurs in cancer cells and has been implicated in the epigenetic silencing of tumor suppressor genes.Here we demonstrate that the human GAD1 promoter were hypermethylated both in cancer cells and in clinical samples that expressed high amounts of GAD1.Inhibition of DNA methyltransferases decreased GAD1 mRNA levels,suggesting that hypermethylation plays a positive role in GAD1 transcription.We further mapped the key region regulate GAD1 expression to an intragenic CpG island and found that the chromatin loop between 5-UTR and the intron 3 mediated by transcription factor CTCF was abolished by DNA methylation.These findings indicated that DNA methylation could activate GAD1 expression by preventing CTCF-mediated silencing.Although DNA methylation at gene promoter often linked to silence tumor suppressor genes in cancer,recent genome-wide methylation studies have markedly changed the conception of DNA methylation negatively regulate gene expression in the mammalian genome.We demonstrated here that hypermethylation prevents CTCF-mediated silencing of GAD 1 by perturbing chromatin-loop formation.This is the first time,to my knowledge,to elucidate the mechanism underlying GAD1 transcription activation in cancer.These results also provide a graphic example of aberrant DNA methylation in cancer should not always be considered as a "silencing marker"for tumor suppressor genes,as it can also serve to promote expression of oncogenes.