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Synthetic lethality with gene silencing

Research Project

Project/Area Number 21H02773
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionHoshi University (2022-2023)
National Cancer Center Japan (2021)

Principal Investigator

Ushijima Toshikazu  星薬科大学, 薬学部, 学長 (90232818)

Co-Investigator(Kenkyū-buntansha) 竹島 秀幸  星薬科大学, 先端生命科学研究所, 特任准教授 (40432497)
山下 聡  国立研究開発法人国立がん研究センター, 研究所, ユニット長 (80321876)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2022: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2021: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywordsエピゲノム / 合成致死 / DNAメチル化
Outline of Research at the Start

申請者は、がん細胞には数多くの遺伝子サイレンシングが存在すること、また、β-catenin阻害と合成致死となるメチル化遺伝子を見いだした。本研究では、第一に、ゲノム内48万のCpG部位のDNAメチル化状態と18,000遺伝子のノックアウトによる細胞生存のデータベースを探索、合成致死となるメチル化サイレンシング遺伝子と標的遺伝子の新しい組み合わせを同定する。さらに、細胞株でのノックダウン・過剰発現等により合成致死を証明する。第二に、遺伝子サイレンシングに影響しないにも関わらず合成致死となるDNAメチル化異常については、核内高次構造・エンハンサー改変・内在性ウイルス活性化等への影響を明らかにする。

Outline of Final Research Achievements

We searched for novel combinations of methylation synthetic lethality, and identified SMARCA1 methylation and inhibition of pyrimidine synthesis pathway. The usefulness of this combination was experimentally validated in vitro. In addition, the causal role of SMARCA1 methylation in the sensitivity to an inhibition of pyrimidine synthesis pathway was also shown.
In addition, as novel target epigenomic alterations other than gene silencing, we identified aberrant methylation of four and 57 enhancers in gastric and lung cancers, respectively, as targets of synthetic lethality.

Academic Significance and Societal Importance of the Research Achievements

本研究から、DNAメチル化異常は突然変異と同様に合成致死に活用することができることが示された。また、SMARCA1は様々ながん種においてDNAメチル化のみならず突然変異においても不活化されているため、がん種横断的な治療開発につながると期待される。
また、従来のプロモーターメチル化以外にもエンハンサーのメチル化も合成致死の起点となり得る可能性が明らかになった。このことから、今までは注目されていなかったゲノム領域の異常でも合成致死に応用できる可能性が考えられる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (27 results)

All 2023 2022 2021

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (22 results) (of which Int'l Joint Research: 6 results,  Invited: 5 results)

  • [Journal Article] A quantification method of somatic mutations in normal tissues and their accumulation in pediatric patients with chemotherapy2022

    • Author(s)
      Ueda Sho、Yamashita Satoshi、Nakajima Miho、Kumamoto Tadashi、Ogawa Chitose、Liu Yu-yu、Yamada Harumi、Kubo Emi、Hattori Naoko、Takeshima Hideyuki、Wakabayashi Mika、Iida Naoko、Shiraishi Yuichi、Noguchi Masayuki、Sato Yukio、Ushijima Toshikazu
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 31

    • DOI

      10.1073/pnas.2123241119

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DNA methylation of the immediate upstream region of BRCA1 major transcription start sites is an independent favorable prognostic factor in patients with high-grade serous ovarian cancer2022

    • Author(s)
      Ebata Takahiro、Yamashita Satoshi、Takeshima Hideyuki、Yoshida Hiroshi、Kawata Yoshiko、Kino Nao、Yasugi Toshiharu、Terao Yasuhisa、Yonemori Kan、Kato Tomoyasu、Ushijima Toshikazu
    • Journal Title

      Gynecologic Oncology

      Volume: 167 Issue: 3 Pages: 513-518

    • DOI

      10.1016/j.ygyno.2022.10.008

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DNA methylation marker to estimate ovarian cancer cell fraction2022

    • Author(s)
      Ebata Takahiro、Yamashita Satoshi、Takeshima Hideyuki、Yoshida Hiroshi、Kawata Yoshiko、Kino Nao、Yasugi Toshiharu、Terao Yasuhisa、Yonemori Kan、Kato Tomoyasu、Ushijima Toshikazu
    • Journal Title

      Medical Oncology

      Volume: 39 Issue: 5 Pages: 78-78

    • DOI

      10.1007/s12032-022-01679-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Influence of degree of DNA degradation in formalin-fixed and paraffin-embedded tissue samples on accuracy of genome-wide DNA methylation analysis2021

    • Author(s)
      Ueda S, Yamashita S, Watanabe S-i, Wakabayashi M, Motoi N, Noguchi M, Sekine S, Sato Y, Ushijima T.
    • Journal Title

      Epigenomics

      Volume: - Issue: 8 Pages: 565-576

    • DOI

      10.2217/epi-2020-0431

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming2021

    • Author(s)
      Hattori Naoko、Asada Kiyoshi、Miyajima Nozomu、Mori Akiko、Nakanishi Yoko、Kimura Kana、Wakabayashi Mika、Takeshima Hideyuki、Nitani Chika、Hara Junichi、Ushijima Toshikazu
    • Journal Title

      British Journal of Cancer

      Volume: 125 Issue: 12 Pages: 1647-1656

    • DOI

      10.1038/s41416-021-01571-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Presentation] Epigenetic field for precision cancer risk diagnosis and exploitation of its carry-over as a synthetic lethal target2023

    • Author(s)
      Ushijima Toshikazu
    • Organizer
      Annual Symposium on ‘60 Years Anniversary of SNUCRI: Past, Present and Future’
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Epigenetic field for precision cancer risk diagnosis and exploitation of its carry-over as a synthetic lethal target2023

    • Author(s)
      Ushijima Toshikazu
    • Organizer
      Singapore Gastric Cancer Consortium 14th Annual Scientific Meeting in 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Methylation synthetic lethality: CHFR methylation and KRAS inhibition in gastric cancers2023

    • Author(s)
      Takeshima Hideyuki、Ebata Takahiro、Furuichi Yumi、Yamashita Satoshi、Ushijima Toshikazu
    • Organizer
      Annual Meeting of AACR
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Screening of methylation synthetic lethality in gastric and colon cancers2023

    • Author(s)
      Furuichi Yumi、Takeshima Hideyuki、Ebata Takahiro、Okano Keiichi、Ushijima Toshikazu
    • Organizer
      Singapore Gastric Cancer Consortium 14th Annual Scientific Meeting in 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] メチル化合成致死:胃がんにおけるCHFRメチル化とKRAS阻害2023

    • Author(s)
      竹島秀幸、江畑貴大、古市ゆみ、山下聡、牛島俊和
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] DNAメチル化を利用したパラログによる合成致死2023

    • Author(s)
      江畑貴大、竹島秀幸、古市ゆみ、牛島俊和
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 胃がん、大腸がんにおけるメチル化合成致死スクリーニング2023

    • Author(s)
      古市ゆみ、竹島秀幸、江畑貴大、岡野圭一、牛島俊和
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] メチル化合成致死:胃がんにおけるCHFRメチル化とKRAS阻害2023

    • Author(s)
      竹島秀幸、江畑貴大、古市ゆみ、大橋由依、奥輝明、山下聡、牛島俊和
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] DNAメチル化を利用したパラログ合成致死2023

    • Author(s)
      江畑貴大、竹島秀幸、古市ゆみ、牛島俊和
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] G0S2メチル化胃がん、大腸がんにおける合成致死スクリーニング2023

    • Author(s)
      古市ゆみ、竹島秀幸、江畑貴大、大橋由依、岡野圭一、牛島俊和
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] CHFRメチル化がん細胞を標的とした合成致死2023

    • Author(s)
      大橋由依、竹島秀幸、江畑貴大、古市ゆみ、益子諒真、奥輝明、牛島俊和
    • Organizer
      第46回日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] DNAメチル化サイレンシングに着目したパラログ合成致死の同定2022

    • Author(s)
      江畑貴大、竹島秀幸、古市ゆみ、牛島俊和
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 消化器がんにおいて遺伝子Aのメチル化は遺伝子B阻害と合成致死を示す2022

    • Author(s)
      古市ゆみ、竹島秀幸、江畑貴大、岡野圭一、牛島俊和
    • Organizer
      第33回日本消化器癌発生学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Methylation synthetic lethality: methylation-silenced genes as a rich source of combination partners for synthetic lethality2022

    • Author(s)
      Ushijima Toshikazu、Yamashita Satoshi、Takeshima Hideyuki、Ebata Takahiro、Furuichi Yumi
    • Organizer
      12th AACR-JCA Joint Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Methylation synthetic lethality: methylation-silenced genes as a rich source of combination partners for synthetic lethality2022

    • Author(s)
      Ushijima Toshikazu
    • Organizer
      6th Asian Cancer Epigenome Meeting on Tackling Cholangiocarcinoma in ASEAN Countries
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] エピゲノム毒性の評価2021

    • Author(s)
      牛島俊和、服部奈緒子
    • Organizer
      第48回日本毒性学会学術年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Cancer epigenetics: mechanisms to clinical applications, and beyond2021

    • Author(s)
      牛島俊和
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Methylation synthetic lethality: large scale isolation of candidate combinationse2021

    • Author(s)
      山下聡、竹島秀幸、牛島俊和
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] HSD17B4遺伝子のDNAメチル化は乳がん細胞の代謝的表現型を変化させる2021

    • Author(s)
      新井信晃、服部奈緒子、山下聡、向井博文、牛島俊和
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ESCC cells with Gene A methylation show synthetic lethality with Gene B inhibition2021

    • Author(s)
      西山和宏、竹島秀幸、山下聡、小濱和貴、牛島俊和
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ESCC cells with Gene C methylation show synthetic lethality with Gene D knockdown2021

    • Author(s)
      Furuichi Yumi、Takeshima Hideyuki、Nishiyama Kazuhiro、Yamashita Satoshi、Okano Keiichi、Ushijima Toshikazu
    • Organizer
      第32回日本消化器癌発生学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Methylation synthetic lethality: large-scale isolation of candidate combinations2021

    • Author(s)
      山下聡、竹島秀幸、牛島俊和
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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