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Pivotal Role of the Chromatin Protein Nupr1 in Kras-Induced Senescence and Transformation. Sci Rep 2015 Nov 30;5:17549 PMID: 26617245 PMCID: PMC4663475

Pubmed ID

26617245

DOI

10.1038/srep17549

Abstract

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 JL

Authors

Gwen Lomberk PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




Scopus

2-s2.0-84948695230   9 Citations

MESH terms used to index this publication - Major topics in bold

Animals
Azacitidine
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)
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad