文章基本信息

标题：Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation
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作者：Daniel Grasso ; Jennifer Bintz ; Gwen Lomberk 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2015
卷号：5
DOI：10.1038/srep17549
出版社：Springer Nature
摘要：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 Nupr1^–/– 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.