The p53 tumor suppressor protein, a sequence specific DNA binding transcription factor, regulates the expression of a large number of genes, in response to various forms of cellular stress. While the protein coding target genes of p53 have been well studied, less is known about its role in regulating long non-coding genes and their functional relevance to cancer. Here we report the genome-wide identification of a large set (>1000) of long non-coding RNAs(lncRNAs) that are putative p53 targets in a colon cancer cell line and in human patient datasets from five different common types of cancer. These lncRNAs have not been annotated by other studies of normal unstressed systems. In the colon cancer cell line a high proportion of these lncRNAs are uniquely induced by different chemotherapeutic agents that activate p53, while others are induced by more than one agent tested. Further, subsets of these lncRNAs independently predict overall and disease-free survival of patients across the five different common cancer types. Interestingly, both genetic alterations and patient survival associated with different lncRNAs are unique to each cancer tested, indicating extraordinary tissue-specific variability in the p53 non-coding response. The newly identified non-coding p53 target genes have allowed us to construct a classifier for tumor diagnosis and prognosis. Implications: Our results not only identify myriad p53-regulated lncRNAs, they also reveal marked drug-induced, as well as tissue- and tumor-specific heterogeneity in these putative p53 targets and our findings have enabled the construction of robust classifiers for diagnosis and prognosis.

中文翻译：

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人类癌症中 p53 调节的长非编码 RNA 的系统表征揭示了不同肿瘤类型之间的显着异质性

p53 肿瘤抑制蛋白是一种序列特异性 DNA 结合转录因子，可调节大量基因的表达，以响应各种形式的细胞应激。虽然 p53 的蛋白质编码靶基因已得到充分研究，但对其在调节长非编码基因中的作用及其与癌症的功能相关性知之甚少。在这里，我们报告了一大组（>1000）长非编码RNA（lncRNA）的全基因组鉴定，这些长非编码RNA（lncRNA）是结肠癌细胞系和来自五种不同常见癌症类型的人类患者数据集中的假定p53靶标。这些 lncRNA 尚未被正常无应激系统的其他研究注释。在结肠癌细胞系中，这些 lncRNA 的很大一部分是由激活 p53 的不同化疗药物独特诱导的，而其他 lncRNA 是由不止一种测试药物诱导的。此外，这些 lncRNA 的子集独立预测五种不同常见癌症类型患者的总体生存率和无病生存率。有趣的是，与不同 lncRNA 相关的基因改变和患者生存率对于每种测试的癌症都是独特的，表明 p53 非编码反应具有非凡的组织特异性变异性。新发现的非编码p53靶基因使我们能够构建用于肿瘤诊断和预后的分类器。意义：我们的结果不仅鉴定了无数 p53 调节的 lncRNA，还揭示了这些假定的 p53 靶标中显着的药物诱导以及组织和肿瘤特异性异质性，我们的研究结果使得能够构建用于诊断和预后的稳健分类器。