RRC ID 51931
Author Diaz-Lagares A, Crujeiras AB, 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, Farré L, Villanueva A, Gross M, Diederichs S, Guil S, Esteller M.
Title Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer.
Journal Proc Natl Acad Sci U S A
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.
Volume 113(47)
Pages E7535-E7544
Published 2016-11-22
DOI 10.1073/pnas.1608585113
PII 1608585113
PMID 27821766
PMC PMC5127373
MeSH Animals Cell Line, Tumor Cell Nucleus / metabolism DNA Damage DNA Methylation DNA-Binding Proteins / genetics* Down-Regulation Epigenesis, Genetic HCT116 Cells Humans Mice Neoplasm Transplantation Neoplasms / genetics* Neoplasms / metabolism Neoplasms / pathology* Prognosis Promoter Regions, Genetic Signal Transduction Tumor Suppressor Protein p53 / metabolism* Y-Box-Binding Protein 1 / genetics Y-Box-Binding Protein 1 / metabolism*
IF 9.58
Times Cited 61
Human and Animal Cells MKN45(RCB1001) MKN7(RCB0999) TGBC11TKB(RCB1148) GCIY(RCB0555)