<i>Neat1</i> is a p53-inducible lincRNA essential for transformation suppression

Abstract

The <i>p53</i> gene is mutated in over half of all cancers, reflecting its critical role as a tumor suppressor. Although p53 is a transcriptional activator that induces myriad target genes, those p53-inducible genes most critical for tumor suppression remain elusive. Here, we leveraged p53 ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) and RNA-seq (RNA sequencing) data sets to identify new p53 target genes, focusing on the noncoding genome. We identify <i>Neat1</i>, a noncoding RNA (ncRNA) constituent of paraspeckles, as a p53 target gene broadly induced by mouse and human p53 in different cell types and by diverse stress signals. Using fibroblasts derived from <i>Neat1</i>^-/- mice, we examined the functional role of <i>Neat1</i> in the p53 pathway. We found that <i>Neat1</i> is dispensable for cell cycle arrest and apoptosis in response to genotoxic stress. In sharp contrast, <i>Neat1</i> plays a crucial role in suppressing transformation in response to oncogenic signals. <i>Neat1</i> deficiency enhances transformation in oncogene-expressing fibroblasts and promotes the development of premalignant pancreatic intraepithelial neoplasias (PanINs) and cystic lesions in Kras^G12D-expressing mice. <i>Neat1</i> loss provokes global changes in gene expression, suggesting a mechanism by which its deficiency promotes neoplasia. Collectively, these findings identify <i>Neat1</i> as a p53-regulated large intergenic ncRNA (lincRNA) with a key role in suppressing transformation and cancer initiation, providing fundamental new insight into p53-mediated tumor suppression.