title: Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid.
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.
authors.affiliation: Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway.
authors.forename: Rakel Brendsdal
authors.initials: RB
authors.lastname: Forthun
authors.forename: Tanima
authors.initials: T
authors.lastname: Sengupta
authors.forename: Hanne Kim
authors.initials: HK
authors.lastname: Skjeldam
authors.forename: Jessica Margareta
authors.initials: JM
authors.lastname: Lindvall
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D051381:Rats; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D006655:Histone Deacetylases