Regulation of CBP and Tip60 coordinates histone acetylation at local and global levels during Ras-induced transformation.
Cell transformation is clearly linked to epigenetic changes. However, the role of the histone-modifying enzymes in this process is still poorly understood. In this study, we investigated the contribution of the histone acetyltransferase (HAT) enzymes to Ras-mediated transformation. Our results demonstrated that lysine acetyltransferase 5, also known as Tip60, facilitates histone acetylation of bulk chromatin in Ras-transformed cells. As a consequence, global H4 acetylation (H4K8ac and H4K12ac) increases in Ras-transformed cells, rendering a more decompacted chromatin than in parental cells. Furthermore, low levels of CREB-binding protein (CBP) lead to hypoacetylation of retinoblastoma 1 (Rb1) and cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27Kip1) tumour suppressor gene promoters to facilitate Ras-mediated transformation. In agreement with these data, overexpression of Cbp counteracts Ras transforming capability in a HAT-dependent manner. Altogether our results indicate that CBP and Tip60 coordinate histone acetylation at both local and global levels to facilitate Ras-induced transformation.
Department of Genomic Regulation, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Baldiri i Reixac 15-21, Parc Científic de Barcelona, E-08028 Barcelona, Spain and Present address: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Fundació Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain.
Sara
S
Sánchez-Molina
Department of Genomic Regulation, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Baldiri i Reixac 15-21, Parc Científic de Barcelona, E-08028 Barcelona, Spain and Present address: University of California, San Diego, La Jolla, CA 92093-0665, USA.
Conchi
C
Estarás
Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain.
José Luis
JL
Oliva
Department of Genomic Regulation, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Baldiri i Reixac 15-21, Parc Científic de Barcelona, E-08028 Barcelona, Spain and Present address: Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, CA 92093-0665, USA.
Naiara
N
Akizu
Department of Genomic Regulation, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Baldiri i Reixac 15-21, Parc Científic de Barcelona, E-08028 Barcelona, Spain and.
Elena
E
Asensio-Juan
Unidad de Biología Celular, Unidad Funcional de Investigación de Enfermedades Crónicas, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain.
José María
JM
Rojas
Department of Genomic Regulation, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Baldiri i Reixac 15-21, Parc Científic de Barcelona, E-08028 Barcelona, Spain and mmbbmc@ibmb.csic.es.
Marian A
MA
Martínez-Balbás
D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D011905:Genes, ras; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D041681:NIH 3T3 Cells / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
C493961:Cdkn1b protein, mouse; D002843:Chromatin; D006657:Histones; D015534:Trans-Activators; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5; D019869:Phosphatidylinositol 3-Kinases