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Development of novel diagnosis and therapy in cancer targetting reversible system of intracellular glycosylation

Research Project

Project/Area Number 19K07762
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionOsaka Medical and Pharmaceutical University

Principal Investigator

Toshihisa Takeuchi  大阪医科薬科大学, 医学部, 准教授 (30445986)

Co-Investigator(Kenkyū-buntansha) 森脇 一将  大阪医科薬科大学, 医学部, 講師 (00467656)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsO-GlcNAc修飾 / FOXM1 / FBXL2 / O-GlcNAc 修飾
Outline of Research at the Start

全ての癌に著効を示す治療薬を、人類は未だに手にできていない。癌を淘汰するには、癌に共通して異常となった幅広い影響力を持つ「システム」を標的にする必要があると、申請者は考える。O-GlcNAc 糖鎖修飾は、グルコース代謝物を基質とする核内細胞質内タンパク質の翻訳後修飾システムであり、その亢進は、癌細胞の特性形成に働いて癌の成長を促進する、癌の基本的特徴である。つまり、O-GlcNAc 修飾を病態レベルから正常レベルに戻す治療は、あらゆる癌治療に応用できる可能性を秘めている。本研究では、胃癌を例に O-GlcNAc 修飾およびその関連分子を標的とした診断および癌治療の可能性を追求する。

Outline of Final Research Achievements

O-GlcNAcylation mediates translational modification through glucose metabolite and is upregulated in cancer cells to promote cancer progression. Many of its target molecules are known and the diverse functions are not fully understood. In this study, we showed that elevated O-GlcNAcylation upregulates expression levels of FOXM1, which is a critical oncogenic transcription factor and its overexpression is associated with poor prognosis of various cancers, via decrease of its ubiquitination. In NUGC-3 human gastric cancer cells, elevated O-GlcNAcylation by OGA (O-GlcNAcase) inhibitor promoted cell proliferation and resistance to some anticancerdrugs. On the contrary, downregulated O-GlcNAcylation by OGT (O-GlcNAc transferase) inhibitor reduced cell proliferation and increased sensitivity to them. These data indicate that elevated O-GlcNAcylation promotes cancer cell proliferation and drug resistance via upregulation of FOXM1, and OGT and FOXM1 are potential targets for cancer therapy.

Academic Significance and Societal Importance of the Research Achievements

癌で上昇するO-GlcNAc修飾は、癌の治療標的として期待されてきたが、O-GlcNAcの標的分子が多岐に渡り、その機能の全容は分かっていなかった。本研究により、O-GlcNAc修飾が、癌の予後不良マーカーとして注目されているFOXM1の発現を制御して癌の進展に強く影響していること、また、抗腫瘍薬の効果をも左右していることが明らかになった。これらの結果は、癌の特性を知り、新しい癌治療の可能性を追求する上で役立つものと期待される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (5 results)

All 2021 2020 2019

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] O-GlcNAcylation-mediated Degradation of FBXL2 Stabilizes FOXM1 to Induce Cancer Progression.2020

    • Author(s)
      Y Ueda, K Moriwaki, T Takeuchi, K Higuchi, and M Asahi.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 521 Issue: 3 Pages: 632-638

    • DOI

      10.1016/j.bbrc.2019.10.164

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] O-GlcNAcylation-mediated regulation of FOXM1 expression through its ubiquitination in a human gastric adenocarcinoma cell line, NUGC-3.2021

    • Author(s)
      K Moriwaki, Y Ueda, T Takeuchi, K Higuchi, and M Asahi.
    • Organizer
      第94回日本薬理学会
    • Related Report
      2020 Research-status Report
  • [Presentation] O-GlcNAcylation-mediated degradation of FBXL2 stabilizes FOXM1 oncogenic transcription factor to promote cancer progression.2020

    • Author(s)
      K Moriwaki, Y Ueda, K Higuchi, and M Asahi.
    • Organizer
      第93回日本薬理学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Elevated O-GlcNAcylation increases FOXM1 protein via suppression of its poly-ubiquitination and subsequent proteasomal degradation.2019

    • Author(s)
      Y Ueda, K Moriwaki, N Sugawara, M Fukumoto, S Harada, K Ota, Y Kojima, T Takeuchi, K Higuchi, and M Asahi.
    • Organizer
      Digestive Disease Week 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Elevated O-GlcNAcylation increases FOXM1 via suppression of FBXL2-mediated its poly-ubiquitination.2019

    • Author(s)
      K Moriwaki, K Higuchi, and M Asahi.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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