ゲノム領域特異的ヒストン修飾の変更技術による新たながんエピゲノムのシステム理解

• Project Area: Integrative Systems Understanding of Cancer for Advanced Diagnosis, Therapy and Prevention
• Project/Area Number: 25134718
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: 永瀬 浩喜 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究所長 (90322073)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: エピゲノム / エピジェネティックス / ヒストン脱アセチル化 / ピロールイミダゾールポリアミド / 化学バイオプローブ / 数理解析 / エピジェネティクス / ヒストン修飾 / ヒストン脱アセチル化酵素阻害剤 / がん

Outline of Annual Research Achievements

エピジェネティックな変化が様々な生物現象に関与し、個々人のがん病態を後天的に規定することが示唆されている。すなわち、環境による影響を受けやすい塩基配列情報以外のエピジェネティックな変化は、がん化に関与すると考えられ、可逆的であり、環境・物質などの外部からの介入により人為的に変更することも可能である。我々はエピジェネティックな変化を塩基配列特異的にコントロールする技術をピロールイミダゾールポリアミド（PIP）とヒストン修飾酵素の阻害剤等の複合体を合成することで実現し、特定のゲノム領域に誘導することに成功している。この技術により、塩基配列特異的にエピゲノム修飾を変更する化学物質をバイオプローブとしてエピジェネティックな変化を一定のゲノムに強制的に導入し、細胞での遺伝子発現や表現型との因果関係や機能を類推することを試みた。細胞の性質を変化させる化合物のランダムスクリーニングにより、細胞を規定する内在性の遺伝子の活性化を探索、エピジェネティクスが関与できる未知の機能関連遺伝子ネットワークの解析を宮野研究室と連携して試みた。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Genome-wide screening of aberrant DNA methylation which associated with gene expression in mouse skin cancers. (2015)
  • Author(s): Fujiwara K, Ghosh S, Liang P, Morien E, Soma M, Nagase H
  • Journal Title: Molecular Carcinogenesis. Volume: e-pub Pages: 1-11
  • DOI: 10.1002/mc.22085
  • Peer Reviewed
• [Journal Article] Runt-related transcription factor 2 (RUNX2) attenuates the transcriptional activity as well as DNA damage-mediated induction of pro-apoptotic TAp73 to regulate chemo-sensitivity. (2015)
  • Author(s): Ozaki T, Sugimoto H, Nakamura M, Hiraoka K, Yoda H, Sang M, Fujiwara K, Nagase H.
  • Journal Title: FEBS J. Volume: 82 Pages: 114-128
  • DOI: 10.1111/febs.13108
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of a novel E-box binding pyrrole-imidazole polyamide inhibiting MYC-driven cell proliferation (2015)
  • Author(s): Mishra R, Watanabe T, Kimura M, Koshikawa N, Ikeda M, Uekusa S, Kawashima H, Wang X, Igarashi J, Choudhury D, Grandori C, Kemp C, Ohira M, Verma N, Kobayashi Y, Takeuchi J, Koshinaga T, Nemoto N, Fukuda N, Soma M, Kusafuka T, Fujiwara K, Nagase H.
  • Journal Title: Cancer Science Volume: 106(4) Pages: 421-429
  • DOI: 10.1111/cas.12610
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of Kras codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate. (2015)
  • Author(s): Hiraoka K, Inoue T, Taylor RD, Watanabe T, Koshikawa N, Yoda H, Shinohara K, Takatori A, Sugimoto H, Maru Y, Denda T, Fujiwara K, Balmain A, Ozaki T, Bando T, Sugiyama H, Nagase H.
  • Journal Title: Nature Communications. Volume: 6 Pages: 6706-6706
  • DOI: 10.1038/ncomms7706
  • NAID: 120006460100
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pyrrole-Imidazole (PI) polyamide-mediated silencing of KCNQ1OT1 expression induces cell death in Wilms tumor cells. (2015)
  • Author(s): Yoshizawa S, Fujiwara K, Sugito K, Uekusa S, Kawashima H, Hoshi R, Watanabe Y, Hirano T, Furuya T, Masuko T, Ueno T, Fukuda N, Soma M, Ozaki T, Koshinaga T, Nagase H.
  • Journal Title: Int J Oncol. Volume: 47(1) Pages: 115-121
  • DOI: 10.3892/ijo.2015.3018
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of malignant phenotypes of human osteosarcoma cells by a gene silencer, a pyrrole–imidazole polyamide, which targets an E-box motif Original Research Article (2014)
  • Author(s): 134. Taniguchi M, Nakai Y, Ozaki T, Koshikawa N, Kojima T, Kataba M, Oguni A, Matsuda H, Yoshida Y, Tokuhashi Y, Fukuda N, Ueno T, Soma T, Nagase H.
  • Journal Title: FEBS OPEN BIO Volume: 4 Pages: 328-334
  • DOI: 10.1016/j.fob.2014.03.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel gene regulator, pyrrole-imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration. (2014)
  • Author(s): Tsunemi A, Ueno T, Fukuda N, Watanabe T, Tahira K, Haketa A, Hatanaka Y, Tanaka S, Matsumoto T, Matsumoto Y, Nagase H, Soma M.
  • Journal Title: J Mol Med Volume: 92 Pages: 509-21
  • Peer Reviewed
• [Journal Article] Inhibition of Human Osteosarcoma Cell Migration and Invasion by a Gene Silencer, Pyrrole–Imidazole Polyamide, Targeted at the Human MMP9 NF-κB Binding Site (2014)
  • Author(s): Kojima T, Wang X, Fujiwara K, Osakaa S, Yoshida Y, Osaka E, Taniguchi M, Ueno T, Fukuda N, Soma M, Tokuhashi Y and Nagase H.
  • Journal Title: Biol. Pharm. Bull. Volume: 37(9) Issue: 9 Pages: 1460-1405
  • DOI: 10.1248/bpb.b14-00147
  • NAID: 130004684785
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of Frequent Differentially Methylated Region in Sporadic Bladder Cancers. (2014)
  • Author(s): Hasegawa R, Fujiwara K, Obinata D, Kawashima H, Shinojima Y, Igarashi J, Wang X, Ghosh S, Nagase H, Takahashi S.
  • Journal Title: Urol Int. Volume: 94(4) Pages: 479-484
  • DOI: 10.1159/000365197
  • Peer Reviewed
• [Journal Article] Pyrrole-imidazole polyamide targeted to break fusion sites in TMPRSS2 and ERG gene fusion represses prostate tumor growth. (2014)
  • Author(s): Obinata D, Ito Akiko, Fujiwara K, Takayama K, Ashikari D, Murata Y, Yamaguchi K, Urano T, Fujimura T, Fukuda N, Soma M, Watanabe T, Nagase H, Inoue S, Takahashi S
  • Journal Title: Cancer Science Volume: 105 Pages: 1272-1278
  • DOI: 10.1111/cas.12493
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Distinct DNA-based epigenetic switches trigger transcriptional activation of (2014)
  • Author(s): Pandian GN, Nagase H
  • Journal Title: Sci. Rep. Volume: 4 Pages: 3843-3843
  • DOI: 10.1038/srep03843
  • Peer Reviewed
• [Journal Article] A synthetic small molecule for targeted transcriptional activation of germ cell genes in a human somatic cell (2013)
  • Author(s): Han L, Pandian GN, Junetha S, Sato S, Anandhakumar C, Taniguchi J, Saha A, Bando T, Nagase H and Sugiyama H.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 52 Pages: 13410-13413
  • DOI: 10.1002/anie.201306766
  • Peer Reviewed
• [Journal Article] Inhibition of MMP-9 by using a pyrrole-imidazole polyamide reduced cell invasion in renal cell carcinoma. (2013)
  • Author(s): Sato A, Nagase H, Obinata D, Fujiwara K, Fukuda N, Soma M, Yamaguchi K, Kawata N, Takahashi S.
  • Journal Title: International Journal of Oncology Volume: 43 Pages: 1441-1446
  • DOI: 10.3892/ijo.2013.2073
  • Peer Reviewed
• [Presentation] ZEB1/E-cadherin 転写制御を標的とした新規ピロールイミダゾールポリアミドの開発 (2014)
  • Author(s): ・養田裕行、高取敦志、渡部隆義、篠原憲一、井上貴博、平岡桐子、越川信子、尾崎俊文、永瀬浩喜
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] MMP-9を標的とした脂肪族/芳香族アミノ酸ペアを有するPIポリアミドによる遺伝子抑制 (2014)
  • Author(s): ・渡部隆義、越川信子、尾崎俊文、板東俊和、杉山弘、永瀬浩喜
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Precision Medicineを目指したオンコジェニックドライバーを標的とした治療 (2014)
  • Author(s): ・永瀬浩喜、平岡桐子、井上隆博、渡部隆義、越川信子、尾崎俊文
  • Organizer: 第23回癌病態治療研究会
  • Place of Presentation: 岐阜
  • Year and Date: 2014-06-12 – 2014-06-13
• [Presentation] A novel alkylating pyrrole‐imidazole polyamide specifically targeting KRAS codon12 mutations preferentially suppresses the malignant phenotypes in colon cancer cells bearing G12D or G12V mutation (2014)
  • Author(s): Hiroki Nagase, Kiriko Hiraoka,Takahiro Inoue,Toshinori Ozaki,Takayoshi Watanabe,Ken-ichi Shinohara,Nobuko Koshokawa
  • Organizer: An AACR Special Conference on RAS ONCOGENES:FROM BIOLOGY TO THERAPY
  • Place of Presentation: オーランド 米国
• [Presentation] 標的ゲノム配列特異的なヒストンアセチル化の誘導 (2013)
  • Author(s): 永瀬浩喜, 越川信子, 渡部隆義
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Remarks] 千葉県がんセンター研究所 がん遺伝創薬研究室
  • URL: http://www.pref.chiba.lg.jp/gan/kenkyujo/soshiki/iden/index.html
• [Remarks] がん研究分野の特性等を踏まえた支援活動
  • URL: http://ganshien.umin.jp/public/research/main/nagase/index.html
• [Patent(Industrial Property Rights)] ドライバーオンコジーンの遺伝子変異を標的にアルキル化する新規アルキル化剤 (2013)
  • Inventor(s): 永瀬浩喜、杉山 弘、板東俊和
  • Industrial Property Rights Holder: 千葉県
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-214044
  • Filing Date: 2013-10-11