期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 47, 页码 E7535-E7544出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1608585113
关键词
DNA methylation; long noncoding RNA; epigenetics; cancer
资金
- European Research Council under the European Community's Seventh Framework Programme (FP7)/ERC [268626/EPINORC]
- Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2011-22803, PI13-01339, SAF2014-55000-R]
- Instituto de Salud Carlos III (ISCIII)
- ERDF Fund A Way to Achieve Europe, under the Integrated Project of Excellence [PIE13/00022]
- Spanish Cancer Research Network (RTICC) [RD12/0036/0039]
- La Marato de TV3 Foundation [20131610]
- Cellex Foundation
- Health and Science Departments of the Catalan Government (Generalitat de Catalunya) AGAUR [2009SGR1315, 2014SGR633]
- Rio Hortega Grant from ISCIII [CM14/00067]
- research contract Sara Borrell [C09/00365]
- CIBERobn from the ISCIII, Spain
- German Research Foundation (DFG) [Di 1421/7-1]
- German Cancer Research Center (DKFZ)
- ICREA Funding Source: Custom
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.
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