Neat1 is a p53-inducible lincRNA essential for transformation suppression

Abstract

The p53 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 Neat1, 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 Neat1 −/− mice, we examined the functional role of Neat1 in the p53 pathway. We found that Neat1 is dispensable for cell cycle arrest and apoptosis in response to genotoxic stress. In sharp contrast, Neat1 plays a crucial role in suppressing transformation in response to oncogenic signals. Neat1 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. Neat1 loss provokes global changes in gene expression, suggesting a mechanism by which its deficiency promotes neoplasia. Collectively, these findings identify Neat1 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.

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer

“…We and others have shown that p53 also directly upregulates several microRNAs including miR-34a and miR-3189 , which, in turn, suppress gene expression downstream of p53 (Chang et al, 2007, Lal et al, 2011, Hermeking, 2012, Jones et al, 2015, Raver-Shapira et al, 2007). More recently, we and others have demonstrated specific functions of a number of p53-regulated lncRNAs, including lincRNA-p21 , PANDA , DINO , PINT , PR-lncRNA-1 , LED , linc-475, NEAT1 and PINCR (Huarte et al, 2010, Dimitrova et al, 2014, Hung et al, 2011, Marin-Bejar et al, 2013, Sanchez et al, 2014, Leveille et al, 2015, Melo et al, 2016, Schmitt et al, 2016, Adriaens et al, 2016, Mello et al, 2017, Chaudhary et al, 2017). Although these studies illustrate the importance of lncRNAs in the p53 network as well as the functional heterogeneity of p53-regulated lncRNAs, the function of the vast majority of p53-regulated lncRNAs remains to be elucidated.…”

“…Therefore, it is difficult to predict whether a given lncRNA is functional or reflects transcriptional noise. LncRNAs are regulated by the same transcription factors that regulate protein-coding genes, and increasing evidence suggests that the master-regulatory transcription factor p53, controls the expression of subset of lncRNAs (Grossi et al, 2016, Chaudhary and Lal, 2016, Adriaens et al, 2016, Mello et al, 2017, Chaudhary et al, 2017). Coordinated regulation of even low-abundance lncRNAs indicates that many lncRNAs have undiscovered, yet critical functions in cell biology and disease.…”

Knockdown long noncoding RNA nuclear paraspeckle assembly transcript 1 suppresses colorectal cancer through modulating miR‐193a‐3p/KRAS

“…52 In pancreatic cancer, NEAT1 was a p53-inducible lncRNA essential to suppress transformation. 53 The paradoxical outcome mirrors labyrinthine controlling networks of NEAT1 and provokes our greater interest in NEAT1.…”

Molecular functions and biological roles of long non‐coding RNAs in human physiology and disease

“…However, Neat1 and paraspeckles are only present in a subpopulation of cells in certain mouse tissues and their loss does not have overt phenotypic effects on development or overall survival in mice, indicating that these nuclear bodies are not essential and only relevant under certain physiologic or pathophysiologic conditions. For example, later studies revealed critical functions for Neat1 in female fertility and lactation, as well as a role in the p53 tumor suppressor pathway and tumorigenesis . However, the mechanism of how Neat1 and paraspeckles regulate these functions in vivo is still unclear.…”

“…For example, later studies revealed critical functions for Neat1 in female fertility and lactation, 75,76 as well as a role in the p53 tumor suppressor pathway and tumorigenesis. [77][78][79] However, the mechanism of how Neat1 and paraspeckles regulate these functions in vivo is still unclear.…”