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

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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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Most cited references 38

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Integration of biological networks and gene expression data using Cytoscape.

Melissa Cline, Michael Smoot, Ethan Cerami … (2007)

Cytoscape is a free software package for visualizing, modeling and analyzing molecular and genetic interaction networks. This protocol explains how to use Cytoscape to analyze the results of mRNA expression profiling, and other functional genomics and proteomics experiments, in the context of an interaction network obtained for genes of interest. Five major steps are described: (i) obtaining a gene or protein network, (ii) displaying the network using layout algorithms, (iii) integrating with gene expression and other functional attributes, (iv) identifying putative complexes and functional modules and (v) identifying enriched Gene Ontology annotations in the network. These steps provide a broad sample of the types of analyses performed by Cytoscape.

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p53 mutations in human cancers.

M Hollstein, D Sidransky, B Vogelstein … (1991)

Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.

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UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

Karl Agger, Paul A. C. Cloos, Jesper Christensen … (2007)

The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.

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Author and article information

Contributors

Ivan Cruz Moura: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2012

Publication date (Electronic): 14 November 2012

Volume: 7

Issue: 11

Electronic Location Identifier: e48992

Affiliations

[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

Author notes

* E-mail: bjorn.gjertsen@ 123456med.uib.no (BTG); hilde.nilsen@ 123456biotek.uio.no (HN)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: BTG HN EM. Performed the experiments: RBF TS HKS EM. Analyzed the data: RBF TS JML HN. Contributed reagents/materials/analysis tools: JML. Wrote the paper: RBF BTG HN.

[¤]

Current address: Huddinge Genomics Core Facilities, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

Article

Publisher ID: PONE-D-12-12362

DOI: 10.1371/journal.pone.0048992

PMC ID: 3498369

PubMed ID: 23155442

SO-VID: 85f0a222-d128-4a77-b23b-7e61067fdf44

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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 credited.

History

Date received : 24 April 2012

Date accepted : 3 October 2012

Page count

Pages: 14

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.

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

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Most cited references 38

Integration of biological networks and gene expression data using Cytoscape.

p53 mutations in human cancers.

UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

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