Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

Angel Diaz-Lagares, Ana B. Crujeiras, Paula Lopez-Serra, Marta Soler, Fernando Setien, Ashish Goyal, Juan Sandoval, Yutaka Hashimoto, Anna Martinez-Cardús, Antonio Gomez, Holger Heyn, Catia Moutinho, Jesús Espada, August Vidal, Maria Paúles, Maica Galán, Núria Sala, Yoshimitsu Akiyama, María Martínez-Iniesta, Lourdes FarréAlberto Villanueva, Matthias Gross, Sven Diederichs, Sonia Guil, Manel Esteller

    Research output: Contribution to journalArticle

    62 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)E7535-E7544
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume113
    Issue number47
    DOIs
    StatePublished - Nov 22 2016

    Keywords

    • Cancer
    • DNA methylation
    • Epigenetics
    • Long noncoding RNA

    ASJC Scopus subject areas

    • General

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  • Cite this

    Diaz-Lagares, A., Crujeiras, A. B., Lopez-Serra, P., Soler, M., Setien, F., Goyal, A., Sandoval, J., Hashimoto, Y., Martinez-Cardús, A., Gomez, A., Heyn, H., Moutinho, C., Espada, J., Vidal, A., Paúles, M., Galán, M., Sala, N., Akiyama, Y., Martínez-Iniesta, M., ... Esteller, M. (2016). Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(47), E7535-E7544. https://doi.org/10.1073/pnas.1608585113