Regulation of CBP and Tip60 coordinates histone acetylation at local and global levels during Ras-induced transformation

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]. 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.The Spanish Ministry of Education and Science (BFU2006-01493, BFU2009-11527, CSD2006-00049, BFU-2012–34261); Fundació La Marató de TV3 (090210); Fondation Jérôme Lejeune to MAMB; the Spanish Ministry of Education and Science, Fondo de Investigaciones Sanitarias-Intrasalud PI09/0562 (SAF2006-04247); Red Temática de Investigación Cooperativa en Cáncer from the Instituto de Salud Carlos III (RD06/0020/0003 and RD12/0036/0021 to J.M.R.); I3P fellowship (I3P-BPD2005) to N.A.; a FPU fellowship to C.E.; and a Generalitat de Catalunya predoctoral fellowship to S.S.-M.Peer Reviewe