Abstract A45: Neat1 is a p53-inducible lincRNA important for pancreatic cancer suppression

Abstract

Abstract p53’s role as a critical tumor suppressor is well illustrated by the fact that it is found mutated in more than half of all human cancers. In addition, the highly penetrant cancer predisposition observed in Li-Fraumeni patients with germline mutations in p53 and in p53 null mice further highlight the importance of p53 in tumor suppression. p53 is a transcription factor, able to sense stress signals such as DNA damage and hyperproliferative signals, promoting in turn the expression of a network of target genes to induce anti-proliferative responses such as cell cycle arrest or apoptosis. Although studies of genes in the p53 network have largely focused on protein-coding genes, in recent years the role of p53-regulated non-coding (nc) RNAs in p53 biology has been increasingly recognized. To identify new p53-regulated ncRNAs that could contribute to tumor suppression, we leveraged chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing (RNA-seq) data we generated previously in p53 wild-type and p53-/- mouse embryonic fibroblasts (MEFs). This analysis uncovered the lincRNA Neat1 as a p53 target gene. We showed that Neat1 is induced by different DNA damaging agents in a p53-dependent manner in different mouse and human cell types, including pancreatic ductal cells. Although we found that Neat1 is not involved in DNA damage-induced p53-dependent cell cycle arrest or apoptosis responses, we found that it does play a role in p53-dependent transformation suppression in both oncogene-expressing fibroblasts and pancreatic cancer cells. Furthermore, using oncogene-expressing fibroblasts, we showed that Neat1 loss promotes cancer in vivo in a subcutaneous xenograft model. Preliminary evidence suggests also that Neat1 loss promotes acinar to ductal metaplasia, bolstering its importance in pancreatic cancer suppression. These findings highlight the importance of Neat1 for p53 tumor suppressor function. Detailed analyses of Neat1’s mechanism of action will provide insights in its function as a tumor suppressor. Citation Format: Stephano S. Mello, Carolyn Sinow, Pawel K. Mazur, Hannes Vogel, John Rinn, Laura D. Attardi.{Authors}. Neat1 is a p53-inducible lincRNA important for pancreatic cancer suppression. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A45.