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Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7535-E7544. Epub 2016 Nov 7.

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

Author information

1
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
2
Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto Salud Carlos III, 28029 Madrid, Spain.
3
Endocrine Division, Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain.
4
Division of RNA Biology and Cancer (B150), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
5
Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
6
Experimental Dermatology and Skin Biology Group, Ramón y Cajal Institute for Biomedical Research (IRYCIS), Ramón y Cajal University Hospital, 28034 Madrid, Spain.
7
Bionanotechnology Laboratory, Bernardo O'Higgins University, Santiago 8370854, Chile.
8
Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, 08907 Barcelona, Catalonia, Spain.
9
Department of Medical Oncology, Catalan Institute of Oncology (ICO), IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
10
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, ICO, IDIBELL, 08908 Barcelona, Catalonia, Spain.
11
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8510 Tokyo, Japan.
12
Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Catalonia, Spain.
13
Laboratory of Experimental Pathology (LAPEX), Gonçalo Moniz Research Center, Oswaldo Cruz Foundation (CPQGM/FIOCRUZ) and National Institute of Science and Technology of Tropical Diseases (INCT/DT), 40296710 Salvador, Bahia, Brazil.
14
Division of Cancer Research, Department of Thoracic Surgery, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
15
Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
16
German Cancer Consortium (DKTK), 79106 Freiburg, Germany.
17
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain; mesteller@idibell.cat sguil@idibell.cat.
18
Departament de Ciències Fisiològiques II, Escola de Medicina, Universitat de Barcelona, 08907 Barcelona, Catalonia, Spain.
19
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain.

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.

KEYWORDS:

DNA methylation; cancer; epigenetics; long noncoding RNA

PMID:
27821766
PMCID:
PMC5127373
DOI:
10.1073/pnas.1608585113
[Indexed for MEDLINE]
Free PMC Article

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