dc.contributor.author | Forthun, Rakel Brendsdal | en_US |
dc.contributor.author | SenGupta, Tanima | en_US |
dc.contributor.author | Skjeldam, Hanne Kim | en_US |
dc.contributor.author | Lindvall, Jessica Margareta | en_US |
dc.contributor.author | McCormack, Emmet | en_US |
dc.contributor.author | Gjertsen, Bjørn Tore | en_US |
dc.date.accessioned | 2013-04-12T11:40:16Z | |
dc.date.available | 2013-04-12T11:40:16Z | |
dc.date.issued | 2012-11-14 | eng |
dc.Published | PLoS ONE 7(11): e48992 | eng |
dc.identifier.issn | 1932-6203 | |
dc.identifier.uri | https://hdl.handle.net/1956/6514 | |
dc.description.abstract | The mechanisms of successful epigenetic reprogramming in cancer are not well characterized as they involve coordinated removal of repressive marks and deposition of activating marks by a large number of histone and DNA modification enzymes. Here, we have used a cross-species functional genomic approach to identify conserved genetic interactions to improve therapeutic effect of the histone deacetylase inhibitor (HDACi) valproic acid, which increases survival in more than 20% of patients with advanced acute myeloid leukemia (AML). Using a bidirectional synthetic lethality screen revealing genes that increased or decreased VPA sensitivity in C. elegans, we identified novel conserved sensitizers and synthetic lethal interactors of VPA. One sensitizer identified as a conserved determinant of therapeutic success of HDACi was UTX (KDM6A), which demonstrates a functional relationship between protein acetylation and lysine-specific methylation. The synthetic lethal screen identified resistance programs that compensated for the HDACi-induced global hyper-acetylation, and confirmed MAPKAPK2, HSP90AA1, HSP90AB1 and ACTB as conserved hubs in a resistance program for HDACi that are drugable in human AML cell lines. Hence, these resistance hubs represent promising novel targets for refinement of combinatorial epigenetic anti-cancer therapy. | en_US |
dc.language.iso | eng | eng |
dc.publisher | Public Library of Science | eng |
dc.rights | Attribution CC BY | eng |
dc.rights.uri | http://creativecommons.org/licenses/by/2.5/ | eng |
dc.title | Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid | en_US |
dc.type | Peer reviewed | |
dc.type | Journal article | |
dc.description.version | publishedVersion | en_US |
dc.rights.holder | Copyright 2012 Forthun et al. | |
dc.identifier.doi | https://doi.org/10.1371/journal.pone.0048992 | |
dc.identifier.cristin | 984524 | |