Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid

• Published in: PloS one Vol. 7; no. 11; p. e48992
• Main Authors: Forthun, Rakel Brendsdal, Sengupta, Tanima, Skjeldam, Hanne Kim, Lindvall, Jessica Margareta, McCormack, Emmet, Gjertsen, Bjørn Tore, Nilsen, Hilde
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.11.2012; PLOS; Public Library of Science (PLoS)
• Subjects: Acetylation; Acids; Acute myeloid leukemia; Analysis; Animals; Apoptosis; Biology; Biotechnology; Caenorhabditis elegans; Cancer; Cancer therapies; Chemotherapy; Chromatin; Combinatorial analysis; Deoxyribonucleic acid; DNA; DNA methylation; Enzymes; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene expression; Genes; Genomic analysis; Genomics; Health aspects; Hematology; Histone deacetylase; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - genetics; Hubs; Humans; Inhibitors; Kinases; Lethality; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Lysine; Medicine; Methylation; Mutation; Myeloid leukemia; Proteins; Rats; Rodents; Valproic acid; Valproic Acid - therapeutic use; Norway
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0048992

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.