dc.date.accessioned | 2020-06-06T18:35:19Z | |
dc.date.available | 2020-06-06T18:35:19Z | |
dc.date.created | 2013-01-09T13:22:20Z | |
dc.date.issued | 2012 | |
dc.identifier.citation | Forthun, Rakel Brendsdal Sengupta, Tanima Skjeldam, Hanne Kim Lindvall, Jessica Margareta Mccormack, Emmet Martin Gjertsen, Bjørn Tore Nilsen, Hilde . Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid. PLOS ONE. 2012, 7(11) | |
dc.identifier.uri | http://hdl.handle.net/10852/76777 | |
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. | |
dc.language | EN | |
dc.publisher | PLOS | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.title | Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid | |
dc.type | Journal article | |
dc.creator.author | Forthun, Rakel Brendsdal | |
dc.creator.author | Sengupta, Tanima | |
dc.creator.author | Skjeldam, Hanne Kim | |
dc.creator.author | Lindvall, Jessica Margareta | |
dc.creator.author | Mccormack, Emmet Martin | |
dc.creator.author | Gjertsen, Bjørn Tore | |
dc.creator.author | Nilsen, Hilde | |
cristin.unitcode | 185,29,21,0 | |
cristin.unitname | Bioteknologisenteret i Oslo | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 1 | |
dc.identifier.cristin | 984524 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=PLOS ONE&rft.volume=7&rft.spage=&rft.date=2012 | |
dc.identifier.jtitle | PLOS ONE | |
dc.identifier.volume | 7 | |
dc.identifier.issue | 11 | |
dc.identifier.doi | https://doi.org/10.1371/journal.pone.0048992 | |
dc.identifier.urn | URN:NBN:no-79862 | |
dc.subject.nvi | VDP::Medisinsk genetikk: 714 | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 1932-6203 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/76777/1/Forthun%2Bet%2Bal%2B2012%252C%2BCross-species%2Bfunctional%2Bgenomic%2Banalysis%2Bidentifies%2Bresistance%2Bgenes%2Bof%2Bthe%2Bhistone%2Bdeacetylase%2Binhibitor%2Bvalproic%2Bacid.pdf | |
dc.type.version | PublishedVersion | |
cristin.articleid | e48992 | |