Villa Raffaella, Pasini Diego, Gutierrez Arantxa, Morey Lluis, Occhionorelli Manuela, Viré Emmanuelle, Nomdedeu Josep F, Jenuwein Thomas, Pelicci Pier Giuseppe, Minucci Saverio, Fuks Francois, Helin Kristian, Di Croce Luciano
Centre de Regulacio Genomica, c/ Dr. Aiguader 88, 08003 Barcelona, Spain.
Cancer Cell. 2007 Jun;11(6):513-25. doi: 10.1016/j.ccr.2007.04.009.
Epigenetic changes are common alterations in cancer cells. Here, we have investigated the role of Polycomb group proteins in the establishment and maintenance of the aberrant silencing of tumor suppressor genes during transformation induced by the leukemia-associated PML-RARalpha fusion protein. We show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA demethylation of PML-RARalpha target genes. This results in promoter reactivation and granulocytic differentiation. Importantly, the epigenetic alterations caused by PML-RARalpha can be reverted by retinoic acid treatment of primary blasts from leukemic patients. Our results demonstrate that the direct targeting of Polycomb group proteins by an oncogene plays a key role during carcinogenesis.
表观遗传变化是癌细胞中常见的改变。在此，我们研究了多梳蛋白家族在白血病相关的PML-RARα融合蛋白诱导的转化过程中，肿瘤抑制基因异常沉默的建立和维持中所起的作用。我们发现，在白血病细胞中，多梳抑制复合物2（PRC2）的关键组分SUZ12的敲低不仅能逆转组蛋白修饰，还能诱导PML-RARα靶基因的DNA去甲基化。这导致启动子重新激活和粒细胞分化。重要的是，白血病患者原代母细胞经维甲酸处理后，PML-RARα引起的表观遗传改变可以被逆转。我们的结果表明，癌基因对多梳蛋白家族的直接靶向作用在致癌过程中起关键作用。
