TY - JOUR
T1 - DNA methylation profiling identifies PTRF/Cavin-1 as a novel tumor suppressor in Ewing sarcoma when co-expressed with caveolin-1
AU - Huertas-Martínez, Juan
AU - Court, Franck
AU - Rello-Varona, Santiago
AU - Herrero-Martín, David
AU - Almacellas-Rabaiget, Olga
AU - Sáinz-Jaspeado, Miguel
AU - Garcia-Monclús, Silvia
AU - Lagares-Tena, Laura
AU - Buj, Raquel
AU - Hontecillas-Prieto, Lourdes
AU - Sastre, Ana
AU - Azorin, Daniel
AU - Sanjuan, Xavier
AU - López-Alemany, Roser
AU - Moran, Sebastian
AU - Roma, Josep
AU - Gallego, Soledad
AU - Mora, Jaume
AU - García del Muro, Xavier
AU - Giangrande, Paloma H.
AU - Peinado, Miquel A.
AU - Alonso, Javier
AU - de Alava, Enrique
AU - Monk, Dave
AU - Esteller, Manel
AU - Tirado, Oscar M.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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, δ-β-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.
AB - 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, δ-β-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.
KW - Apoptosis
KW - Caveolae
KW - Cavin-1
KW - DNA methylation
KW - Ewing sarcoma
KW - PTRF
UR - http://www.scopus.com/inward/record.url?scp=85004011399&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2016.11.020
DO - 10.1016/j.canlet.2016.11.020
M3 - Article
C2 - 27894957
SN - 0304-3835
VL - 386
SP - 196
EP - 207
JO - Cancer Letters
JF - Cancer Letters
ER -
