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Epigenetic regulation of iron trafficking in glioblastoma

Research Project

Project/Area Number 17K15672
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Experimental pathology
Research InstitutionTokyo Women's Medical University

Principal Investigator

Masui Kenta  東京女子医科大学, 医学部, 助教 (60747682)

Research Collaborator MISCHEL Paul  
Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords悪性脳腫瘍 / mTOR複合体 / エピジェネティクス / ヒストンアセチル化 / 中心炭素代謝 / 鉄代謝 / mTORC2 / がん代謝 / 微量元素 / 膠芽腫
Outline of Final Research Achievements

Aberrant growth factor receptor signaling remodels intracellular metabolism and global gene transcription to drive aggressive cancer growth, but the underlying mechanisms are not well understood. Here we show that in the highly malignant brain tumor glioblastoma (GBM), mammalian target of rapamycin complex 2 (mTORC2), a critical effector of the growth factor signaling system, links metabolic reprogramming and acetyl-CoA production with genome-wide alteration of histone acetylation. Integrated analyses in mouse models and human GBM samples demonstrate that mTORC2 regulates iron trafficking via histone H3 acetylation of the ferritin promoter, promoting tumor cell proliferation and survival. These results nominate mTORC2 as a critical epigenetic regulator of iron metabolism in cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究は、悪性度が高く有効な治療法がない脳腫瘍である膠芽腫において、腫瘍細胞内の鉄代謝の制御機構に着目することで、新しい治療戦略の可能性を探索する独創的な試みである。細胞を使った基礎的な実験に加えて、実際のヒト脳腫瘍標本を用いる病理組織学的解析を行うことで、悪性脳腫瘍の病態に関わる鉄代謝という基礎的な分子メカニズムが、本研究により診断・治療を含む臨床応用まで視野に入れた形で解明されることが期待される。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (16 results)

All 2019 2018 2017 Other

All Journal Article (4 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (11 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Remarks (1 results)

  • [Journal Article] Metabolic reprogramming in the pathogenesis of glioma: Update2019

    • Author(s)
      Masui Kenta、Onizuka Hiromi、Cavenee Webster K.、Mischel Paul S.、Shibata Noriyuki
    • Journal Title

      Neuropathology

      Volume: 39 Issue: 1 Pages: 3-13

    • DOI

      10.1111/neup.12535

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression2018

    • Author(s)
      Harachi Mio、Masui Kenta、Okamura Yukinori、Tsukui Ryota、Mischel Paul、Shibata Noriyuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 10 Pages: 3267-3267

    • DOI

      10.3390/ijms19103267

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Elevated TERT Expression in TERT-Wildtype Adult Diffuse Gliomas: Histological Evaluation with a Novel TERT-Specific Antibody.2018

    • Author(s)
      Masui K, Komori T, Kato Y, Masutomi K, Ichimura K, Ogasawara S, Kaneko MK, Oki H, Suzuki H, Nitta M, Maruyama T, Muragaki Y, Kawamata T, Sawada T, and Shibata N
    • Journal Title

      BioMed Research International

      Volume: - Pages: 95-99

    • DOI

      10.1155/2018/7945845

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular and Genetic Determinants of Glioma Cell Invasion2017

    • Author(s)
      Masui Kenta、Kato Yoichiro、Sawada Tatsuo、Mischel Paul、Shibata Noriyuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 18 Issue: 12 Pages: 2609-2609

    • DOI

      10.3390/ijms18122609

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] がん細胞における微量元素代謝のエピジェネティック制御機構2018

    • Author(s)
      増井憲太, 鬼塚裕美, Paul S. Mischel, 柴田亮行
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒストン修飾がもたらす悪性脳腫瘍の病態-がん代謝のエピジェネティック制御-2018

    • Author(s)
      増井 憲太, 柴田 亮行
    • Organizer
      第59回日本組織細胞化学会総会・学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] mTORC2-dependent metabolic reprogramming facilitates epigenetic regulation of iron trafficking in glioblastoma2018

    • Author(s)
      Kenta Masui, Paul Mischel, Noriyuki Shibata
    • Organizer
      19th International Congress of Neuropathology (ICN2018 Tokyo)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] mTORC2 links metabolic reprogramming with epigenetic regulation of iron trafficking in glioblastoma2018

    • Author(s)
      Kenta Masui, Paul Mischel, Noriyuki Shibata
    • Organizer
      22nd International Conference on Brain Tumor Research and Therapy
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] がん細胞における鉄代謝のエピジェネティック制御2018

    • Author(s)
      増井憲太, Paul S. Mischel, 柴田亮行
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] がん細胞におけるエピジェネティクス変化と鉄代謝2018

    • Author(s)
      増井憲太
    • Organizer
      第22回日本がん分子標的治療学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 悪性脳腫瘍における代謝経路の網羅的解析2017

    • Author(s)
      増井憲太、原地美緒、Paul S. Mischel、柴田亮行
    • Organizer
      第35回日本脳腫瘍病理学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 悪性脳腫瘍における微量元素代謝の新規制御機序2017

    • Author(s)
      増井憲太、原地美緒、Paul S. Mischel、柴田亮行
    • Organizer
      第58回日本神経病理学会総会学術研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 悪性脳腫瘍の病態に関わる新規代謝経路の網羅的探索2017

    • Author(s)
      増井憲太、原地美緒、Paul S. Mischel、柴田亮行
    • Organizer
      第5回がんと代謝研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] mTOR複合体を介する糖代謝と微量元素代謝のクロストーク2017

    • Author(s)
      増井憲太、原地美緒、Paul S. Mischel、柴田亮行
    • Organizer
      第12回臨床ストレス応答学会
    • Related Report
      2017 Research-status Report
  • [Presentation] mTORC2とがん代謝:中心炭素代謝から微量元素代謝へ2017

    • Author(s)
      増井憲太、原地美緒、Paul S. Mischel、柴田亮行
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Remarks] 東京女子医科大学 医学部 病理学講座 (病態神経科学分野)

    • URL

      http://www.twmu.ac.jp/Basic/patho1/

    • Related Report
      2018 Annual Research Report

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Published: 2017-04-28   Modified: 2020-03-30  

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