Sánchez Yolanda, Segura Victor, Marín-Béjar Oskar, Athie Alejandro, Marchese Francesco P, González Jovanna, Bujanda Luis, Guo Shuling, Matheu Ander, Huarte Maite
Center for Applied Medical Research, University of Navarra, 55 Pio XII Avenue, 31008 Pamplona, Spain.
Department of Gastroenterology, Donostia Hospital-Biodonostia Research Institute, University of Basque Country (UPV/EHU), Biomedical Research Center in the Network of Digestive and Hepatic Diseases (CIBERehd), Dr Begiristain Square, 20014 San Sebastian, Spain.
Nat Commun. 2014 Dec 19;5:5812. doi: 10.1038/ncomms6812.
Despite the inarguable relevance of p53 in cancer, genome-wide studies relating endogenous p53 activity to the expression of lncRNAs in human cells are still missing. Here, by integrating RNA-seq with p53 ChIP-seq analyses of a human cancer cell line under DNA damage, we define a high-confidence set of 18 lncRNAs that are p53 transcriptional targets. We demonstrate that two of the p53-regulated lncRNAs are required for the efficient binding of p53 to some of its target genes, modulating the p53 transcriptional network and contributing to apoptosis induction by DNA damage. We also show that the expression of p53-lncRNAs is lowered in colorectal cancer samples, constituting a tumour suppressor signature with high diagnostic power. Thus, p53-regulated lncRNAs establish a positive regulatory feedback loop that enhances p53 tumour suppressor activity. Furthermore, the signature defined by p53-regulated lncRNAs supports their potential use in the clinic as biomarkers and therapeutic targets.
尽管p53在癌症中的相关性无可争议，但关于人类细胞中内源性p53活性与lncRNA表达之间关系的全基因组研究仍属空白。在此，通过整合RNA测序与对DNA损伤下的人类癌细胞系进行的p53染色质免疫沉淀测序分析，我们确定了一组由18个lncRNA组成的高可信度集合，它们是p53的转录靶点。我们证明，p53调控的lncRNA中的两个对于p53有效结合其某些靶基因是必需的，可调节p53转录网络并促进DNA损伤诱导的细胞凋亡。我们还表明，p53-lncRNA在结直肠癌样本中的表达降低，构成了具有高诊断能力的肿瘤抑制特征。因此，p53调控的lncRNA建立了一个增强p53肿瘤抑制活性的正调控反馈环。此外，由p53调控的lncRNA定义的特征支持它们在临床上作为生物标志物和治疗靶点的潜在用途。
