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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE45232 | GEO | 2013/07/01

SECONDARY ACCESSION(S): PRJNA193289

REPOSITORIES: GEO

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Project description:The objective of this study was to elucidate the role of Nupr1 in pancreatic tumorigenesis. Using the Pdx-1-cre;LSL-KrasG12D mouse as model we discovered that, in contrast to KrasG12D pancreas that develop multiple foci of pancreatic intraepithelial neoplasia (PanIN), KrasG12D;Nupr1KO pancreas were free from such lesions, indicating that Nupr1 is pivotal for PanIN formation. In vitro, MiaPaCa2 cells activated Nupr1 expression in response to nutrient deprivation and this expression was necessary for cell survival. Mechanistically, Nupr1 protected cells from stress-induced death by inhibiting apoptosis through an alternative RelBàIER3-dependent pathway and independent from activation of the classical RelA-based NF-kB pathway. In agreement with these findings, Nupr1, RelB and IER3 proteins were found co-expressed in PanINs from KrasG12D pancreas. Moreover, pancreas-specific KrasG12D;RelbDpanc mice displayed a delay in PanIN development associated with a lack of IER3 expression, further emphasizing the relevance of this pathway in vivo. Efficient PanIN formation was therefore dependent on the expression of Nupr1 and RelB, with the probable involvement of IER3. Finally, a significant correlation between expression of Nupr1, RelB and IER3 and a poor prognosis of patients with PDAC was found. Altogether, our results reveal a novel stress-related pathway that requires the functional interaction of Nupr1àRelBàIER3 in KrasG12D-dependent transformation of the pancreas and expand our understanding of the molecular machinery that mediates the early steps of pancreatic carcinogenesis. Since Nupr1 belongs to the HMG family of chromatin remodelers with transcriptional co-factor activity, Nupr1 could increase cell survival in a nutrient-deprived microenvironment by activating the expression of pro-survival genes. Moreover, considering that RelB, and not RelA/p65, is essential to the Nupr1-mediated survival mechanism that takes place upon nutrient deprivation-induced stress, we made the hypothesis that the two NF-kB transcription factors should activate different sets of genes among which a pivotal pro-survival gene would be exclusively dependent on RelB. In order to test this two hypothesis, an Affymetrix microarray analysis was performed using pancreatic cancer cells transfected with siCtrl or siNupr1 and cultured for 3, 6 or 9 hrs in EBSS; or transfected with siRelB, siRelA/p65 or siCtrl and cultured for 9 hrs in EBSS or Mock.

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

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