文章基本信息

标题：Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer
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作者：Angel Diaz-Lagares ; Ana B. Crujeiras ; Paula Lopez-Serra 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：E7535-E7544
DOI：10.1073/pnas.1608585113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceLong noncoding RNAs (lncRNAs) are starting to be recognized as critical molecules for cellular transformation, although only a few candidates have so far been characterized. Here we report that TP53TG1 is an lncRNA that is critical for the correct response of p53 to DNA damage. The cancer growth suppressor features of TP53TG1 are linked to its ability to block the tumorigenic activity of the RNA binding protein YBX1. The DNA methylation-associated silencing of TP53TG1 produces aggressive tumors that are resistant to cellular death when DNA-damaging agents and small targeted molecules are used. Our study provides an example of a tumor suppressor lncRNA undergoing an epigenetic lesion in cancer that is placed at the crossroads of DNA damage and oncogenic pathways. Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell.
关键词：DNA methylation ; long noncoding RNA ; epigenetics ; cancer