TY - JOUR
T1 - Neat1 is a p53-inducible lincRNA essential for transformation suppression
AU - Mello, Stephano S.
AU - Sinow, Carolyn
AU - Raj, Nitin
AU - Mazur, Pawel K.
AU - Bieging-Rolett, Kathryn
AU - Broz, Daniela Kenzelmann
AU - Imam, Jamie F.Conklin
AU - Vogel, Hannes
AU - Wood, Laura D.
AU - Sage, Julien
AU - Hirose, Tetsuro
AU - Nakagawa, Shinichi
AU - Rinn, John
AU - Attardi, Laura D.
N1 - Funding Information:
We thank J.C. Marine, B.M. Flowers, and A. Kaiser for critical discussions and reading of the manuscript. We thank P. Chu of the Stanford Comparative Medicine Histology Research Core Laboratory for technical assistance with tissue processing, sectioning, and staining; A. Fox and G. Pierron for plasmids; N. Bardeesy for p53-deficient pancreatic cancer cells; J.C. Marine for Neat1 knockout MEFs; and E. Majunder for technical assistance. This work was supported by funding from the National Institutes of Health (R01 ES020260 to J.R. and L.D.A., and R35 CA197591 to L.D.A.) and the Lustgarten Foundation (J.S.).
Publisher Copyright:
© 2017 Mello et al.
PY - 2017
Y1 - 2017
N2 - 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 neopla-sias (PanINs) and cystic lesions in KrasG12D-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.
AB - 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 neopla-sias (PanINs) and cystic lesions in KrasG12D-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.
KW - LincRNA
KW - Neat1
KW - P53
KW - Pancreatic cancer
KW - Tumor suppression
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U2 - 10.1101/gad.284661.116
DO - 10.1101/gad.284661.116
M3 - Article
C2 - 28698299
AN - SCOPUS:85025098628
SN - 0890-9369
VL - 31
SP - 1095
EP - 1108
JO - Genes and Development
JF - Genes and Development
IS - 11
ER -