Super-enhancer and dynamic chromatine remodeling in gliomagenesis

• Project/Area Number: 16H05436
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Nagoya University
• Principal Investigator: Natsume Atsushi 名古屋大学, 医学系研究科, 准教授 (30362255)
• Co-Investigator(Kenkyū-buntansha): 近藤 豊 名古屋大学, 医学系研究科, 教授 (00419897) ; 若林 俊彦 名古屋大学, 医学系研究科, 教授 (50220835) ; 小川 誠司 京都大学, 医学研究科, 教授 (60292900)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 脳腫瘍 / エピゲノム / ヒストン / EZH2 / ポリコーム / ゲノム / 脳腫瘍学 / 創薬 / 癌 / ゲノム構造 / スーパーエンハンサー

Outline of Final Research Achievements

Although isocitrate dehydrogenase (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 generated a glioma mouse model, which concurrently lacks p53 and NF1 and develops tumors highly comparable with human IDH-wild-type DAG without characteristic molecular features of glioblastoma. During tumor formation, Ezh2 was upregulated and histone H3K27me3 was increased on target genes. Inhibition of Ezh2 activity effectively repressed tumor growth in vivo. Our study clarifies a pathogenic molecular pathway of IDH-wild-type DAG that depends on Ezh2 activity, and that targeting Ezh2 might be a promising treatment option for this type of glioma.

Academic Significance and Societal Importance of the Research Achievements

悪性脳腫瘍のゲノム解析により細分類されている。従来の抗がん剤治療が有効なものもあるが、未だ予後不良なものがある。予後不良な脳腫瘍はゲノム異常が十分解明されていないため、有効な治療法が見出せないでいることが原因のひとつである。我々は、抗がん剤の無効な脳腫瘍のゲノム異常から惹起されるエピゲノム異常を明らかにした。その中でヒストン修飾をするEZH2の異常を発見し、EZH2に対する阻害剤が有効であることを解明した。

Research Products

• [Int'l Joint Research] ソウル大学(韓国)
• [Journal Article] Posterior Cerebral Artery Reconstruction by In-Situ Bypass with Superior Cerebellar Artery via Occipital Transtentorial Approach (2019)
  • Author(s): Tanahashi Kuniaki、Araki Yoshio、Uda Kenji、Muraoka Shinsuke、Motomura Kazuya、Lushun Chalise、Wakabayashi Toshihiko、Natsume Atsushi
  • Journal Title: World Neurosurgery Volume: 126 Pages: 24-29
  • DOI: 10.1016/j.wneu.2019.02.127
  • Peer Reviewed
• [Journal Article] Multiplex ligation-dependent probe amplification analysis is useful for detecting a copy number gain of the FGFR1 tyrosine kinase domain in dysembryoplastic neuroepithelial tumors. (2019)
  • Author(s): Matsumura N, Nobusawa S, Ito J, Kakita A, Suzuki H, Fujii Y, Fukuda M, Iwasaki M, Nakasato N, Tominaga T, Natsume A, Mikami Y, Shinojima N, Yamazaki T, Nakazato Y, Hirato J, Yokoo H.
  • Journal Title: J Neurooncol. Volume: 143 Issue: 1 Pages: 27-33
  • DOI: 10.1007/s11060-019-03138-7
  • Peer Reviewed
• [Journal Article] Aberrant Active cis-Regulatory Elements Associated with Downregulation of RET Finger Protein Overcome Chemoresistance in Glioblastoma (2019)
  • Author(s): Ranjit Melissa、Hirano Masaki、Aoki Kosuke、Okuno Yusuke、Ohka Fumiharu、Yamamichi Akane、Kato Akira、Maeda Sachi、Motomura Kazuya、Matsuo Keitaro、Enomoto Atsushi、Ino Yasushi、Todo Tomoki、Takahashi Masahide、Wakabayashi Toshihiko、Kato Takuya、Natsume Atsushi
  • Journal Title: Cell Reports Volume: 26 Issue: 9 Pages: 2274-2281
  • DOI: 10.1016/j.celrep.2019.01.109
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma. (2018)
  • Author(s): Narita Y, Arakawa Y, Yamasaki F, Nishikawa R, Aoki T, Kanamori M, Nagane M, Kumabe T, Hirose Y, Ichikawa T, Kobayashi H, Fujimaki T, Goto H, Takeshima H, Ueba T, Abe H, Tamiya T, Sonoda Y, Natsume A, Kakuma T, Sugita Y, Komatsu N, Yamada A, Sasada T, Matsueda S, Shichijo S, Itoh K, Terasaki M.
  • Journal Title: Neuro Oncol. Volume: 21 Issue: 3 Pages: 348-359
  • DOI: 10.1093/neuonc/noy200
  • Peer Reviewed / Open Access
• [Journal Article] Pediatric-type follicular lymphoma in the dura: a case report and literature review. (2018)
  • Author(s): Yamaguchi J, Kato S, Iwata E, Aoki K, Kabeya R, Natsume A, Wakabayashi T.
  • Journal Title: World Neurosurg. Volume: 印刷中 Pages: 176-180
  • DOI: 10.1016/j.wneu.2018.04.053
  • Peer Reviewed
• [Journal Article] Neuro-endoscopic cylinder surgery and 5-aminolevulinic acid (5-ALA) photodynamic diagnosis of deep-seated intracranial lesions. (2018)
  • Author(s): Choo J, Takeuchi K, Nagata Y, Ohka F, Kishida Y, Watanabe T, Satoh Y, Nagatani T, Kato K, Wakabayashi T, Natsume A.
  • Journal Title: World Neurosurg. Volume: 印刷中 Pages: e35-e41
  • DOI: 10.1016/j.wneu.2018.03.112
  • Peer Reviewed
• [Journal Article] Podoplanin - an emerging cancer biomarker and therapeutic target. (2018)
  • Author(s): Krishnan H, Rayes J, Miyashita T, Ishii G, Retzbach EP, Sheehan SA, Takemoto A, Chang YW, Yoneda K, Asai J, Jensen L, Chalise L, Natsume A, Goldberg GS.
  • Journal Title: Cancer Sci. Volume: 印刷中 Issue: 5 Pages: 1292-1299
  • DOI: 10.1111/cas.13580
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunohistochemical ATRX expression is not a surrogate for 1p19q codeletion (2018)
  • Author(s): Yamamichi Akane、Ohka Fumiharu、Aoki Kosuke、Suzuki Hiromichi、Kato Akira、Hirano Masaki、Motomura Kazuya、Tanahashi Kuniaki、Chalise Lushun、Maeda Sachi、Wakabayashi Toshihiko、Kato Yukinari、Natsume Atsushi
  • Journal Title: Brain Tumor Pathology Volume: - Issue: 2 Pages: 106-113
  • DOI: 10.1007/s10014-018-0312-5
  • NAID: 120006496406
  • Peer Reviewed
• [Journal Article] A novel high-sensitivity assay to detect a small fraction of mutant IDH1 using droplet digital PCR (2018)
  • Author(s): Hirano Masaki、Ohka Fumiharu、Maeda Sachi、Chalise Lushun、Yamamichi Akane、Aoki Kosuke、Kato Akira、Tanahashi Kuniaki、Motomura Kazuya、Nishimura Yusuke、Hara Masahito、Shinjo Keiko、Kondo Yutaka、Wakabayashi Toshihiko、Natsume Atsushi
  • Journal Title: Brain Tumor Pathology Volume: - Issue: 2 Pages: 97-105
  • DOI: 10.1007/s10014-018-0310-7
  • Peer Reviewed / Open Access
• [Journal Article] Elevation of autoantibody level against PDCD11 in patients with transient ischemic attack (2017)
  • Author(s): Yoshida Y, Wang H, Hiwasa T, Machida T, Takiguchi M, Iwadate Y, et al.
  • Journal Title: Oncotarget Volume: 9 Issue: 3 Pages: 8836-8848
  • DOI: 10.1007/s11060-018-2831-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of a novel fusion gene HMGA2-EGFR in glioblastoma (2017)
  • Author(s): Komuro Akiyoshi、Raja Erna、Iwata Caname、Soda Manabu、Isogaya Kazunobu、Yuki Keiko、Ino Yasushi、Morikawa Masato、Todo Tomoki、Aburatani Hiroyuki、Suzuki Hiromichi、Ranjit Melissa、Natsume Atsushi、Mukasa Akitake、Saito Nobuhito、Okada Hitoshi、Mano Hiroyuki、Miyazono Kohei、Koinuma Daizo
  • Journal Title: International Journal of Cancer Volume: 142 Issue: 8 Pages: 1627-1639
  • DOI: 10.1002/ijc.31179
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic relevance of genetic alterations in diffuse lower-grade gliomas (2017)
  • Author(s): Aoki Kosuke、Nakamura Hideo、Suzuki Hiromichi et al.
  • Journal Title: Neuro-Oncology Volume: 20 Issue: 1 Pages: 66-77
  • DOI: 10.1093/neuonc/nox132
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oncogenic effects of evolutionarily conserved noncoding RNA ECONEXIN on gliomagenesis (2017)
  • Author(s): Deguchi S、Katsushima K、Hatanaka A、Shinjo K、Ohka F、Wakabayashi T、Zong H、Natsume A、Kondo Y
  • Journal Title: Oncogene Volume: 36 Issue: 32 Pages: 4629-4640
  • DOI: 10.1038/onc.2017.88
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic effects of evolutionarily conserved noncoding RNA ECONEXIN on gliomagenesis. (2017)
  • Author(s): Deguchi S, Katsushima K, Hatanaka A, Shinjo K, Ohka F, Wakabayashi T, Zong H, Natsume A, Kondo Y.
  • Journal Title: Oncogene. Volume: 印刷中 Issue: 1
  • DOI: 10.1186/s12934-017-0682-0
  • Peer Reviewed
• [Journal Article] Synthesis of PET probe O6-[(3-[11C]methyl)benzyl]guanine by Pd0-mediated rapid C-[11C]methylation toward imaging DNA repair protein O6-methylguanine-DNA methyltransferase in glioblastoma. (2017)
  • Author(s): Koyama H, Ikenuma H, Toda H, Kondo G, Hirano M, Kato M, Abe J, Yamada T, Wakabayashi T, Ito K, Natsume A, Suzuki M.
  • Journal Title: Bioorg Med Chem Lett. Volume: 27 Issue: 9 Pages: 1892-1896
  • DOI: 10.1016/j.bmcl.2017.03.045
  • NAID: 120006331834
  • Peer Reviewed
• [Journal Article] A novel all-in-one intraoperative genotyping system for IDH1-mutant glioma. (2017)
  • Author(s): Ohka F, Yamamichi A, Kurimoto M, Motomura K, Tanahashi K, Suzuki H, Aoki K, Deguchi S, Chalise L, Hirano M, Kato A, Nishimura Y, Hara M, Kato Y, Wakabayashi T, Natsume A.
  • Journal Title: Brain Tumor Pathol. Volume: 印刷中 Issue: 2 Pages: 91-97
  • DOI: 10.1007/s10014-017-0281-0
  • NAID: 120006331835
  • Peer Reviewed
• [Journal Article] Development of Database and Genomic Medicine for von Hippel-Lindau Disease in Japan (2017)
  • Author(s): Takayanagi S, Mukasa A, Nakatomi H, Kanno H, Kuratsu JI, Nishikawa R, Mishima K, Natsume A, Wakabayashi T, Houkin K, Terasaka S, Yao M, Shinohara N, Shuin T, Saito N.
  • Journal Title: Neurologia medico-chirurgica Volume: 57 Issue: 2 Pages: 59-65
  • DOI: 10.2176/nmc.ra.2016-0206
  • NAID: 130005394576
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access
• [Journal Article] Surgical benefits of combined awake craniotomy and intraoperative magnetic resonance imaging for gliomas associated with eloquent areas. (2017)
  • Author(s): Motomura K, Natsume A, Iijima K, Kuramitsu S, Fujii M, Yamamoto T, Maesawa S, Sugiura J, Wakabayashi T.
  • Journal Title: J Neurosurg. Volume: 印刷中
  • Peer Reviewed
• [Presentation] Neurofibromatosis 1と神経膠腫のゲノム解明とNF1変異動物モデルの表現型 (2019)
  • Author(s): 夏目敦至、大岡史治、若林俊彦、近藤 豊
  • Organizer: 第10回日本レックリングハウゼン病学
  • Invited
• [Presentation] immune-cold”と言われる脳腫瘍に対する免疫治療を考える (2019)
  • Author(s): 夏目敦至、大岡史治、若林俊彦、近藤 豊
  • Organizer: 第５回名古屋大学がん免疫フォーラ
  • Invited
• [Presentation] Mathematical prediction for precision medicine of CNS glial tumors (2019)
  • Author(s): Atsushi Natsume
  • Organizer: AACR-JCA joint meeting
  • Int'l Joint Research
• [Presentation] グリオーマでのクローン進化を数理モデル (2018)
  • Author(s): 夏目敦至、大岡史治、若林俊彦、近藤 豊
  • Organizer: 第10回 がんゲノム・エピゲノム、数理統計解析についての勉強会
  • Invited
• [Presentation] State of art treatment for brain cancer using single cell atlas and artificial intelligence (2018)
  • Author(s): Atsushi Natsume
  • Organizer: 日越国交45周年記念祝賀
  • Int'l Joint Research / Invited
• [Presentation] ゲノム時代におけるグリオーマの治療戦略 (2018)
  • Author(s): 夏目敦至
  • Organizer: 第22回北海道脳腫瘍懇話会
  • Invited
• [Presentation] Genome-based Precision Medicine in Brain Tumors (2018)
  • Author(s): Atsushi Natsume
  • Organizer: First Joint US-Japan Clinical Cancer Genomics and Personalized Medicine Symposium
  • Int'l Joint Research / Invited
• [Presentation] Mutational landscape and clonal architecture (2017)
  • Author(s): Atsushi Natsume
  • Organizer: Chemistry of Molecular Crowding
  • Int'l Joint Research / Invited
• [Presentation] ゲノムから見た低悪性度神経膠腫の手術のdecision making (2016)
  • Author(s): 夏目敦至
  • Organizer: 脳腫瘍治療セミナー
  • Place of Presentation: 東京
  • Year and Date: 2016-06-10
  • Int'l Joint Research / Invited
• [Presentation] グリオーマの遺伝生物学と最新の免疫治療の展望 (2016)
  • Author(s): 夏目敦至
  • Organizer: 第36回日本脳神経外科コングレス総会
  • Place of Presentation: 大阪
  • Year and Date: 2016-05-21
  • Int'l Joint Research / Invited
• [Presentation] 脳腫瘍 迅速診断遺伝子検査の意義 (2016)
  • Author(s): 夏目敦至
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台、宮城県
  • Year and Date: 2016-05-14
  • Int'l Joint Research / Invited
• [Presentation] 脳腫瘍の網羅的ゲノム解析と個別化診断医療 (2016)
  • Author(s): 夏目敦至
  • Organizer: 第３回バイオセンシングコンソーシアム
  • Place of Presentation: 東京
  • Year and Date: 2016-05-10
  • Int'l Joint Research / Invited
• [Presentation] Genetic biomarkers to predict prognosis and kinetics of clonal evolution by mathematical computational modeling in low-grade glioma (2016)
  • Author(s): Atsushi Natsume
  • Organizer: International Brain Tumor Research and Therapy
  • Place of Presentation: 那覇、沖縄県
  • Year and Date: 2016-04-12
  • Int'l Joint Research / Invited