Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer.
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.
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Angel
A
Diaz-Lagares
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.|Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto Salud Carlos III, 28029 Madrid, Spain.|Endocrine Division, Complejo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain.
Ana B
AB
Crujeiras
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Paula
P
Lopez-Serra
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Marta
M
Soler
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Fernando
F
Setien
Division of RNA Biology and Cancer (B150), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Ashish
A
Goyal
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Juan
J
Sandoval
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Yutaka
Y
Hashimoto
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Anna
A
Martinez-Cardús
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Antonio
A
Gomez
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Holger
H
Heyn
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Catia
C
Moutinho
Experimental Dermatology and Skin Biology Group, Ramón y Cajal Institute for Biomedical Research (IRYCIS), Ramón y Cajal University Hospital, 28034 Madrid, Spain.|Bionanotechnology Laboratory, Bernardo O'Higgins University, Santiago 8370854, Chile.
Jesús
J
Espada
Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, 08907 Barcelona, Catalonia, Spain.
August
A
Vidal
Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet de Llobregat, 08907 Barcelona, Catalonia, Spain.
Maria
M
Paúles
Department of Medical Oncology, Catalan Institute of Oncology (ICO), IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Catalonia, Spain.
Maica
M
Galán
Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, ICO, IDIBELL, 08908 Barcelona, Catalonia, Spain.
Núria
N
Sala
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 113-8510 Tokyo, Japan.
Yoshimitsu
Y
Akiyama
Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Catalonia, Spain.
María
M
Martínez-Iniesta
Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Catalonia, Spain.|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.
Lourdes
L
Farré
Program Against Cancer Therapeutic Resistance (ProCURE), ICO, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Catalonia, Spain.
Alberto
A
Villanueva
Division of RNA Biology and Cancer (B150), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Matthias
M
Gross
Division of RNA Biology and Cancer (B150), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.|Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.|Division of Cancer Research, Department of Thoracic Surgery, Medical Center-University of Freiburg, 79106 Freiburg, Germany.|Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.|German Cancer Consortium (DKTK), 79106 Freiburg, Germany.
Sven
S
Diederichs
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.
Sonia
S
Guil
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.|Departament de Ciències Fisiològiques II, Escola de Medicina, Universitat de Barcelona, 08907 Barcelona, Catalonia, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain.
Manel
M
Esteller
D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C495901:TP53 protein, human; C114495:TP53TG1 protein, human; D016159:Tumor Suppressor Protein p53; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human
DNA methylation; cancer; epigenetics; long noncoding RNA