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

PLoS One. 2012;7(11):e48992. doi: 10.1371/journal.pone.0048992. Epub 2012 Nov 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Epigenesis, Genetic
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Histone Deacetylases / genetics
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics*
  • Rats
  • Valproic Acid / therapeutic use*

Substances

  • Histone Deacetylase Inhibitors
  • Valproic Acid
  • Histone Deacetylases

Grants and funding

This work was supported by grants from The National Program for Research in Functional Genomics at The Research Council of Norway (H.N., H.K.S., B.T.G., and R.B.F.), Helse Vest grants (E.M.C.), and a grant from the Norwegian Cancer Society. H.N. and T.S. were supported by the University of Oslo and the Norwegian Cancer Society. R.B.F. was a recipient of EU COST action CANGENIN BM0703 and C. elegans NordForsk Travel grants. B.T.G. participates in COST action EuGESMA BM0801. H.N. and B.T.G. participate in COST action BM0703 and Nordforsk Network on Genomic Integrity. J.M.L. was the recipient of an Exchange Grant (no. 3054) from the European Science Foundation Research Networking Programme Frontiers of Functional Genomics (FFG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.