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

Abstract

Gliomas are classified by combining histopathologic and molecular features, including isocitrate dehydrogenase (<i>IDH</i>) status. Although <i>IDH</i>-wild-type diffuse astrocytic glioma (DAG) shows a more aggressive phenotype than <i>IDH</i>-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 <i>IDH</i>-wild-type DAGs and a glioma mouse model with a mosaic analysis with double markers (MADM) system, which concurrently lacks <i>p53</i> and <i>NF1</i> and spontaneously develops tumors highly comparable with human <i>IDH</i>-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 (<i>Fzd8</i>), 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 <i>Fzd8</i>, together with significant reduction of tumor size. Our study clarifies a pathogenic molecular pathway of <i>IDH</i>-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 <i>IDH</i>-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.