Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation. Sci Rep 2015 Nov 30;5:17549
Date
12/01/2015Pubmed ID
26617245Pubmed Central ID
PMC4663475DOI
10.1038/srep17549Scopus ID
2-s2.0-84948695230 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
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.
Author List
Grasso D, Bintz J, Lomberk G, Molejon MI, Loncle C, Garcia MN, Lopez MB, Urrutia R, Iovanna JLAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinRaul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAzacitidine
Cell Line, Tumor
Cell Transformation, Neoplastic
Cellular Senescence
CpG Islands
DNA Methylation
DNA-Binding Proteins
Dynamin I
Gene Expression Regulation, Neoplastic
Gene Silencing
Humans
Lung Neoplasms
Mice
Mice, Knockout
Neoplasm Proteins
Oncogenes
Pancreatic Neoplasms
Promoter Regions, Genetic
Proto-Oncogene Proteins p21(ras)