Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
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DOI：
10.1038/srep17549
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发表时间：
2015-11-30
影响因子：
4.6
通讯作者：
Iovanna, Juan L.
中科院分区：
文献类型：
--
作者：
Grasso, Daniel;Bintz, Jennifer;Iovanna, Juan L.
Nupr 1是一种染色质蛋白，它与Kras（G12 D）合作，诱导PanIN形成和小鼠胰腺癌的发展，尽管这种作用的分子机制仍有待充分表征。在目前的研究中，我们报告说，Nupr 1作为一种基因修饰剂的Kras（G12 D）诱导的衰老的影响，通过调节Dnmt 1的表达，从而在全基因组范围内的DNA甲基化水平。相应地，DNA甲基化的一般抑制剂5-氮杂-2 '-脱氧胞苷通过促进衰老逆转Kras（G12 D）诱导的PanIN发育。然而，Nupr 1表达的这种要求并不限于胰腺，因为在Nupr（-/-）小鼠的肺中，Kras（G12 D）的表达诱导衰老而不是转化。因此，从机制上讲，这些数据表明，表观遗传事件，至少在DNA甲基化水平，调节常见的基因突变，如Kras（G12 D），在癌变过程中的功能结果。这些发现的生物医学相关性在于，它们支持在人类中开发旨在控制癌症的开始或进展的类似治疗干预的合理性。
Nupr1 is a chromatin protein, which cooperates with Kras(G12D) to induce PanIN formation and pancreatic cancer development in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we report that Nupr1 acts as a gene modifier of the effect of Kras(G12D)-induced senescence by regulating Dnmt1 expression and consequently genome-wide levels of DNA methylation. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the Kras(G12D)-induced PanIN development by promoting senescence. This requirement of Nupr1 expression, however, is not restricted to the pancreas since in lung of Nupr(-/-) mice the expression of Kras(G12D) induces senescence instead of transformation. Therefore, mechanistically this data reveals that epigenetic events, at least at the level of DNA methylation, modulate the functional outcome of common genetic mutations, such as Kras(G12D), during carcinogenesis. The biomedical relevance of these findings lies in that they support the rational for developing similar therapeutic interventions in human aimed at controlling either the initiation or progression of cancer.