00085472can191272-sup-221109_2_supp_5657874_pqwcny.xlsx (67.44 kB)

Supplementary Tables from Pathogenic Epigenetic Consequences of Genetic Alterations in IDH-Wild-Type Diffuse Astrocytic Gliomas

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posted on 2023-03-31, 02:47 authored by Fumiharu Ohka, Keiko Shinjo, Shoichi Deguchi, Yusuke Matsui, Yusuke Okuno, Keisuke Katsushima, Miho Suzuki, Akira Kato, Noboru Ogiso, Akane Yamamichi, Kosuke Aoki, Hiromichi Suzuki, Shinya Sato, Nirmala Arul Rayan, Shyam Prabhakar, Jonathan Göke, Teppei Shimamura, Reo Maruyama, Satoru Takahashi, Akio Suzumura, Hiroshi Kimura, Toshihiko Wakabayashi, Hui Zong, Atsushi Natsume, Yutaka Kondo

ST1: Primer list; ST2: The most differentially expressed 401 transcripts (top 1%) in MADM tumors compared with normal brains; ST3: Upregulated 544 genes specifically in MADM tumors not in GL261; ST4: The mutational and expression status of 162 epigenome-associated genes in LGGs and GBMs; ST5: Significantly upregulated and downregulated genes by Ezh2 depletion; ST6: Representative genes with H3K4me3 alone, H3K27me3 alone or bivalent modifications in Ezh2 wild-type P8 precancerous cells and Ezh2 wild-type MADM tumor cells (top 50 genes with highest relative value); ST7: Gene ontology of upregulated genes by Ezh2 depletion.

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Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

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ARTICLE 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. EZH2 is involved in the generation of IDH-wild-type diffuse astrocytic gliomas and is a potential therapeutic target for this type of glioma.

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Keywords

Cns Cancers Gliomas, Glioblastomas Drug Targets Oncoprotein & tumor suppressor drug targets Gene Regulation Transcriptional control of cell differentiation

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