Reciprocal modulation of long noncoding RNA EMS and p53 regulates tumorigenesis
Menée in vitro et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel la protéine p53 et le facteur de stabilisation du long ARN non codant E2F1, en agissant chacun sur l'expression de l'autre, régulent la tumorigenèse
As a master transcription factor, the tumor suppressor p53 regulates a variety of cellular processes by modulating target gene expression. Although well known as a transcriptional activator, p53 is also able to repress expression of a number of protein-coding genes. However, it remains largely unknown whether long noncoding RNA (lncRNA) gene repression is involved in the regulation of p53 function. Here, we show that p53 can transcriptionally repress expression of the lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and vice versa and that EMS can suppress p53 translation and negatively regulate p53 function. Our study reveals an important double-negative feedback loop that controls p53 activity and provides insights into the mechanisms whereby EMS promotes tumorigenesis.p53 plays a central role in tumor suppression. Emerging evidence suggests long noncoding RNA (lncRNA) as an important class of regulatory molecules that control the p53 signaling. Here, we report that the oncogenic lncRNA E2F1 messenger RNA (mRNA) stabilizing factor (EMS) and p53 mutually repress each other’s expression. EMS is negatively regulated by p53. As a direct transcriptional repression target of p53, EMS is surprisingly shown to inhibit p53 expression. EMS associates with cytoplasmic polyadenylation element-binding protein 2 (CPEB2) and thus, disrupts the CPEB2–p53 mRNA interaction. This disassociation attenuates CPEB2-mediated p53 mRNA polyadenylation and suppresses p53 translation. Functionally, EMS is able to exert its oncogenic activities, at least partially, via the CPEB2–p53 axis. Together, these findings reveal a double-negative feedback loop between p53 and EMS, through which p53 is finely controlled. Our study also demonstrates a critical role for EMS in promoting tumorigenesis via the negative regulation of p53.All study data are included in the article and/or SI Appendix.