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Cancer Res. 2019 Oct 1;79(19):4814-4827. doi: 10.1158/0008-5472.CAN-19-1272. Epub 2019 Aug 20.

Pathogenic Epigenetic Consequences of Genetic Alterations in IDH-Wild-Type Diffuse Astrocytic Gliomas.

Author information

1
Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
2
Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
3
Laboratory of Intelligence Healthcare, Nagoya University Graduate School of Medicine, Nagoya, Japan.
4
Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
5
Laboratory of Experimental Animal, National Center for Geriatrics and Gerontology (NCGG), Obu, Japan.
6
Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
7
Computational and Systems Biology, Genome Institute of Singapore, Singapore, Singapore.
8
Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
9
Project for Cancer Epigenomics, Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan.
10
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
11
Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan.
12
Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia.
13
Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. ykondo@med.nagoya-u.ac.jp anatsume@med.nagoya-u.ac.jp.
14
Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. ykondo@med.nagoya-u.ac.jp anatsume@med.nagoya-u.ac.jp.
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Contributed equally

Abstract

Gliomas are classified by combining histopathologic and molecular features, including isocitrate dehydrogenase (IDH) status. Although IDH-wild-type diffuse astrocytic glioma (DAG) shows a more aggressive phenotype than IDH-mutant type, lack of knowledge regarding relevant molecular drivers for this type of tumor has hindered the development of therapeutic agents. Here, we examined human IDH-wild-type DAGs and a glioma mouse model with a mosaic analysis with double markers (MADM) system, which concurrently lacks p53 and NF1 and spontaneously develops tumors highly comparable with human IDH-wild-type DAG without characteristic molecular features of glioblastoma (DAG-nonMF). During tumor formation, enhancer of zeste homolog (EZH2) and the other polycomb repressive complex 2 (PRC2) components were upregulated even at an early stage of tumorigenesis, together with an increased number of genes with H3K27me3 or H3K27me3 and H3K4me3 bivalent modifications. Among the epigenetically dysregulated genes, frizzled-8 (Fzd8), which is known to be a cancer- and stem cell reprogramming-related gene, was gradually silenced during tumorigenesis. Genetic and pharmacologic inhibition of EZH2 in MADM mice showed reactivation of aberrant H3K27me3 target genes, including Fzd8, together with significant reduction of tumor size. Our study clarifies a pathogenic molecular pathway of IDH-wild-type DAG-nonMF that depends on EZH2 activity and provides a strong rationale for targeting EZH2 as a promising therapeutic approach for this type of glioma. SIGNIFICANCE: EZH2 is involved in the generation of IDH-wild-type diffuse astrocytic gliomas and is a potential therapeutic target for this type of glioma. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4814/F1.large.jpg.

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