A Genetic-to-Epigenetic Crosstalk Plays a Pivotal Role in the Promotion of KrasG12D-Induced Senescence and PanIN formation

Nupr1 is a chromatin protein which cooperates with KrasG12D to induce PanIN formation in mice, though the molecular mechanisms underlying this effect remain to be fully characterized. In the current study, we find that Nupr1 acts as a gene modifier of the effect of KrasG12D-induced senescence by regulating Dnmt1 expression, changing the genome-wide levels of DNA methylation and activating the growth regulatory FoxO3a-Skp2-p27Kip1-pRb-E2F pathway. Congruently, 5-aza-2'-deoxycytydine, a general inhibitor of DNA methylation, reverses the KrasG12D-induced PanIN development through an effect on oncogene-induced senescence. Therefore, mechanistically this data reveals that epigenetic events modulate the functional outcome of genetic mutations during the progression of pancreatic cancer. The fact that small drug inhibitors of these epigenetic pathways reverse the effects triggered by genetic changes lends significant biomedical relevance to this knowledge for the future design of novel therapies aimed at controlling the progression of pancreatic cancer. The pancreatic gene expression profile of Nupr1 (+/+) Kras-G12D mouse was compared to the Nupr1 (-/-) Kras-G12D mouse.