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Cell ; 150(6): 1135-46, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-22980977

RESUMO

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.


Assuntos
Citosina/análogos & derivados , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Nevo/genética , 5-Metilcitosina/análogos & derivados , Citosina/metabolismo , Proteínas de Ligação a DNA/genética , Dioxigenases , Estudo de Associação Genômica Ampla , Humanos , Isocitrato Desidrogenase/genética , Melanócitos/metabolismo , Melanoma/patologia , Nevo/patologia , Proteínas Proto-Oncogênicas/genética
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