Di Croce Luciano, Raker Veronica A, Corsaro Massimo, Fazi Francesco, Fanelli Mirco, Faretta Mario, Fuks Francois, Lo Coco Francesco, Kouzarides Tony, Nervi Clara, Minucci Saverio, Pelicci Pier Giuseppe
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
Science. 2002 Feb 8;295(5557):1079-82. doi: 10.1126/science.1065173.
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.
肿瘤抑制基因的DNA甲基化是癌症中转录沉默的常见机制。甲基化特异性的潜在分子机制尚不清楚。我们在此报告，促白血病的PML-RAR融合蛋白通过将DNA甲基转移酶招募至靶启动子来诱导基因超甲基化和沉默，且超甲基化有助于其致白血病潜能。维甲酸处理可诱导启动子去甲基化、基因重新表达以及转化表型的逆转。这些结果在转化过程中的遗传和表观遗传变化之间建立了机制联系，并表明超甲基化有助于癌症发生的早期步骤。
