Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor
Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor
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DOI：
10.1126/science.1065173
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发表时间：
2002-02-08
期刊：
影响因子：
56.9
通讯作者：
Pelicci, PG
中科院分区：
文献类型：
--
作者：
Di Croce, L;Raker, VA;Pelicci, PG
肿瘤抑制基因的DNA甲基化是肿瘤中转录沉默的常见机制。甲基化特异性的分子机制尚不清楚。我们在这里报告，白血病促进PML-RAR融合蛋白诱导基因超甲基化和沉默招募DNA甲基转移酶的目标启动子和超甲基化有助于其白血病的潜力。视黄酸处理诱导启动子去甲基化、基因再表达和转化表型的逆转。这些结果建立了转化过程中遗传和表观遗传变化之间的机制联系，并表明超甲基化有助于癌发生的早期步骤。
DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential. Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. These results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis.