Cross-Species Functional Genomic Analysis Identifies Resistance Genes of the Histone Deacetylase Inhibitor Valproic Acid |
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| Authors: | Rakel Brendsdal Forthun Tanima SenGupta Hanne Kim Skjeldam Jessica Margareta Lindvall Emmet McCormack Bj?rn Tore Gjertsen Hilde Nilsen |
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| Institution: | 1. Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway.; 2. The Biotechnology Centre, University of Oslo, Oslo, Norway.; 3. Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen, Norway.; Institut national de la santé et de la recherche médicale (INSERM), France, |
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| 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. |
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