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Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid

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 appro...

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Autores principales: Forthun, Rakel Brendsdal, SenGupta, Tanima, Skjeldam, Hanne Kim, Lindvall, Jessica Margareta, McCormack, Emmet, Gjertsen, Bjørn Tore, Nilsen, Hilde
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498369/
https://www.ncbi.nlm.nih.gov/pubmed/23155442
http://dx.doi.org/10.1371/journal.pone.0048992
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author Forthun, Rakel Brendsdal
SenGupta, Tanima
Skjeldam, Hanne Kim
Lindvall, Jessica Margareta
McCormack, Emmet
Gjertsen, Bjørn Tore
Nilsen, Hilde
author_facet Forthun, Rakel Brendsdal
SenGupta, Tanima
Skjeldam, Hanne Kim
Lindvall, Jessica Margareta
McCormack, Emmet
Gjertsen, Bjørn Tore
Nilsen, Hilde
author_sort Forthun, Rakel Brendsdal
collection PubMed
description 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.
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spelling pubmed-34983692012-11-15 Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid Forthun, Rakel Brendsdal SenGupta, Tanima Skjeldam, Hanne Kim Lindvall, Jessica Margareta McCormack, Emmet Gjertsen, Bjørn Tore Nilsen, Hilde PLoS One Research Article 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. Public Library of Science 2012-11-14 /pmc/articles/PMC3498369/ /pubmed/23155442 http://dx.doi.org/10.1371/journal.pone.0048992 Text en © 2012 Forthun et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Forthun, Rakel Brendsdal
SenGupta, Tanima
Skjeldam, Hanne Kim
Lindvall, Jessica Margareta
McCormack, Emmet
Gjertsen, Bjørn Tore
Nilsen, Hilde
Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid
title Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid
title_full Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid
title_fullStr Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid
title_full_unstemmed Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid
title_short Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid
title_sort cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498369/
https://www.ncbi.nlm.nih.gov/pubmed/23155442
http://dx.doi.org/10.1371/journal.pone.0048992
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