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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

Publicly Offered Research

Project AreaIntegrative 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 TypeSingle-year Grants
Review Section Complex systems
Research InstitutionChiba 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 *help
¥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。

Report

(2 results)
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (21 results)

All 2015 2014 2013 Other

All Journal Article (13 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 13 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (5 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [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-sensitivity2015

    • Author(s)
      Ozaki T, Sugimoto H, Nakamura M, Hiraoka K, Yoda H, Sang M, Fujiwara K, Nagase H.
    • Journal Title

      FEBS Journal

      Volume: 82 Issue: 1 Pages: 114-28

    • DOI

      10.1111/febs.13108

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Identification of a novel E-box binding PI 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) Issue: 4 Pages: 421-429

    • DOI

      10.1111/cas.12610

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

      International Journal of Oncology

      Volume: 47(1) Issue: 1 Pages: 115-121

    • DOI

      10.3892/ijo.2015.3018

    • Related Report
      2014 Annual Research Report
    • 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 E-box.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 Issue: 1 Pages: 328-334

    • DOI

      10.1016/j.fob.2014.03.004

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel gene regulator, pyrrole-imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration2014

    • 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

      Journal of Molecular Medicine

      Volume: 92 Issue: 5 Pages: 509-521

    • DOI

      10.1007/s00109-013-1118-x

    • Related Report
      2014 Annual Research Report
    • 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 Site2014

    • 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

      Biological and Pharmaceutical Bulletin

      Volume: 37 Issue: 9 Pages: 1460-1465

    • DOI

      10.1248/bpb.b14-00147

    • NAID

      130004684785

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [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) Issue: 4 Pages: 479-484

    • DOI

      10.1159/000365197

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pyrrole-imidazole polyamide targeted to break fusion sites in TMPRSS2 and ERG gene fusion represses prostate tumor growth2014

    • 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 Sci

      Volume: 105 Issue: 10 Pages: 1272-1278

    • DOI

      10.1111/cas.12493

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate.2014

    • 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

      Nat. Commun.

      Volume: 6 Issue: 1 Pages: 6706-6706

    • DOI

      10.1038/ncomms7706

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct DNA-based epigenetic switches trigger differential transcriptional activation in human dermal fibroblasts2014

    • Author(s)
      Pandian GN, Nagase H
    • Journal Title

      Scientific Reports

      Volume: 4 Issue: 1 Pages: 3843-3843

    • DOI

      10.1038/srep03843

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genome-wide screening of aberrant DNA methylation which associated with gene expression in mouse skin cancers2013

    • Author(s)
      Fujiwara K, Ghosh S, Liang P, Morien E, Soma M, Nagase H
    • Journal Title

      Molecular Carcinogenesis

      Volume: e-pub Issue: 3 Pages: 1-11

    • DOI

      10.1002/mc.22085

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Synthetic Small Molecule Enforces 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

      Angewandte Chemie

      Volume: 52 Issue: 50 Pages: 13410-13413

    • DOI

      10.1002/anie.201306766

    • Related Report
      2013 Annual Research Report
    • 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 Issue: 5 Pages: 1441-1446

    • DOI

      10.3892/ijo.2013.2073

    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
  • [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 mutation2014

    • 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
    • Related Report
      2013 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report
  • [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

    • Related Report
      2013 Annual Research Report
  • [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

    • Related Report
      2013 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report

URL: 

Published: 2013-05-15   Modified: 2019-07-29  

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