DNA methylation profiling identifies PTRF/Cavin-1 as a novel tumor suppressor in Ewing sarcoma when co-expressed with caveolin-1
Por:
Huertas-Martinez, J, Court, F, Rello-Varona, S, Herrero-Martin, D, Almacellas-Rabaiget, O, Sainz-Jaspeado, M, Garcia-Monclus, S, Lagares-Tena, L, Buj, R, Hontecillas-Prieto, L, Sastre, A, Azorin, D, Sanjuan, X, Lopez-Alemany, R, Moran, S, Roma, J, Gallego, S, Mora, J, del Muro, XG, Giangrande, PH, Peinado, MA, Alonso, J, de Alava, E, Monk, D, Esteller, M and Tirado, OM
Publicada:
1 feb 2017
Resumen:
Epigenetic modifications have been shown to be important in developmental tumors as Ewing sarcoma. We profiled the DNA methylation status of 15 primary tumors, 7 cell lines, 10 healthy tissues and 4 human mesenchymal stem cells lines samples using the Infinium Human Methylation 450K. Differential methylation analysis between Ewing sarcoma and reference samples revealed 1166 hypermethylated and 864 hypomethylated CpG sites (Bonferroni p < 0.05, delta-beta-value with absolute difference of >0.20) corresponding to 392 and 470 genes respectively. Gene Ontology analysis of genes differentially methylated in Ewing sarcoma samples showed a significant enrichment of developmental genes. Membrane and cell signal genes were also enriched, among those, 11 were related to caveola formation. We identified differential hypermethylation of CpGs located in the body and S-Shore of the PTRF gene in Ewing sarcoma that correlated with its repressed transcriptional state. Reintroduction of PTRF/Cavin-1 in Ewing sarcoma cells revealed a role of this protein as a tumor suppressor. Restoration of caveolae in the membrane of Ewing sarcoma cells, by exogenously reintroducing PTRF, disrupts the MDM2/p53 complex, which consequently results in the activation of p53 and the induction of apoptosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Filiaciones:
Huertas-Martinez, J:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Court, F:
Inst Invest Biomed Bellvitge IDIBELL, Canc Epigenet & Biol Programme PEBC, Barcelona 08908, Spain
Rello-Varona, S:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Herrero-Martin, D:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Almacellas-Rabaiget, O:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Sainz-Jaspeado, M:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Garcia-Monclus, S:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Lagares-Tena, L:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Buj, R:
Inst Germans Trias & Pujol, Program Predict & Personalized Med Canc IMPPC, Barcelona 08916, Spain
Hontecillas-Prieto, L:
Inst Biomed Sevilla IBiS, Lab Mol Pathol, Seville 41013, Spain
Sastre, A:
Hosp Univ La Paz, Unidad Hematol & Oncol Pediat, Madrid, Spain
Azorin, D:
Hosp Infantil Univ Nino Jesus, Serv Anat Patol, Madrid 28009, Spain
Sanjuan, X:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Hosp Univ Bellvitge, Dept Pathol, Barcelona 08908, Spain
Lopez-Alemany, R:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Moran, S:
Inst Invest Biomed Bellvitge IDIBELL, Canc Epigenet & Biol Programme PEBC, Barcelona 08908, Spain
Roma, J:
Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst, Lab Translat Res Pediat Canc, Barcelona 08035, Spain
Gallego, S:
Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst, Lab Translat Res Pediat Canc, Barcelona 08035, Spain
Mora, J:
Hosp St Joan de Deu, Dev Tumor Biol Lab, Barcelona 08950, Spain
del Muro, XG:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
Inst Catala Oncol, Sarcoma Multidisciplinary Unit, Barcelona 08908, Spain
Giangrande, PH:
Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA
:
Inst Germans Trias & Pujol, Program Predict & Personalized Med Canc IMPPC, Barcelona 08916, Spain
Alonso, J:
ISCIII, Inst Invest Enfermedades Raras, Unidad Tumores Solidos Infantiles, Madrid 28029, Spain
de Alava, E:
Inst Biomed Sevilla IBiS, Lab Mol Pathol, Seville 41013, Spain
Univ Seville, CSIC, Hosp Univ Virgen del Rocio, Seville 41013, Spain
Monk, D:
Inst Invest Biomed Bellvitge IDIBELL, Canc Epigenet & Biol Programme PEBC, Barcelona 08908, Spain
Esteller, M:
Inst Invest Biomed Bellvitge IDIBELL, Canc Epigenet & Biol Programme PEBC, Barcelona 08908, Spain
Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona, Catalonia, Spain
Inst Catalana Recerca & Estudis Avancats, Barcelona, Catalonia, Spain
Tirado, OM:
Inst Invest Biomed Bellvitge IDIBELL, Sarcoma Res Grp, Barcelona 08908, Spain
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