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Spatial and temporal regulation mechanism and its role of TGFbeta-induced Myc overexpression in osteosarcoma development and progression

Research Project

Project/Area Number 22K21066
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0907:Oral science and related fields
Research InstitutionNagasaki University

Principal Investigator

Ueno Tomoya  長崎大学, 医歯薬学総合研究科(歯学系), 助教 (40968583)

Project Period (FY) 2022-08-31 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords骨肉腫 / Runx / c-Myc / TGFβ / Runx3 / p53 / TGF-β
Outline of Research at the Start

先行研究によって、骨肉腫発症の根幹は、がん抑制遺伝子p53の欠損下で転写因子Runx3誘導性に、がん遺伝子c-Mycが過剰発現することにあると判明した。しかし、この機序を惹起する因子は不明のままであった。
腫瘍微小環境では、炎症性サイトカインが腫瘍悪性化因子として機能するとされている。そこで、p53欠損骨肉腫細胞で高い発現が見られたサイトカインTGFβに着目し、解析を進めたところ、TGFβが、Mycスーパーエンハンサー上に転写因子複合体の形成を誘導し、Runx3依存的なMyc過剰発現を惹起していることが分かった。本研究では、この転写因子複合体の形成機序と骨肉腫発症・進展における役割を解明する。

Outline of Final Research Achievements

We recently demonstrated that p53 inactivation and Myc overexpression, which are essential for OS development, are mediated by Runx transcription factors. However, the mechanisms inducing Myc upregulation by Runx in a p53-deficient microenvironment remain unclear.
We found that p53 disruption causes TGFβ to aberrantly induce Myc in osteoprogenitors. We identified its cognate enhancer (super enhancer) downstream of the Myc gene, which interacted with the Myc promoter upon TGFβ stimulation via chromatin looping.At this region, TGFβ promoted the occupancy of each member of a transcriptional complex consisting of Runx, its cooperative factors, AP1 and Smads, and CBP, further activating the enhancer by H3K27ac deposition.
These results suggest that Myc dysregulation are mediated by the epigenetic node, where TGFβ plays a pivotal role in collaboration with Runx to unleash Myc.

Academic Significance and Societal Importance of the Research Achievements

がん抑制遺伝子p53とがん遺伝子Mycは、ヒトの悪性腫瘍に広く関わる代表的な遺伝子であり、これらを取り巻く分子機序の解明に多くの研究者が取り組んでいる。そのため、p53とMycがRunxやTGFβによって仲介されることを示した本研究成果は、骨肉腫以外の悪性腫瘍の研究にも繋がるだろう。特に、Myc過剰発現誘導の中核を成すTGFβ作動性転写装置は、骨肉腫だけでなく、他の悪性腫瘍の治療標的となる可能性を秘めている。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (3 results)

All 2023 2022

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (2 results)

  • [Journal Article] C/ebpα represses the oncogenic Runx3?Myc axis in p53-deficient osteosarcoma development2023

    • Author(s)
      Omori Keisuke、Otani Shohei、Date Yuki、Ueno Tomoya、Ito Tomoko、Umeda Masahiro、Ito Kosei
    • Journal Title

      Oncogene

      Volume: 42 Issue: 33 Pages: 2485-2494

    • DOI

      10.1038/s41388-023-02761-z

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Presentation] TGFβ signaling facilitates Myc upregulation by Runx in p53-deficient osteosarcoma development2022

    • Author(s)
      Kosei Ito, Tomoya Ueno, Shohei Otani, Yuki Date
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Research-status Report
  • [Presentation] TGFβシグナルはp53欠損骨肉腫において、RunxによるMyc過剰誘導を促進する2022

    • Author(s)
      上野智也、伊達悠貴、伊藤公成
    • Organizer
      第35回発癌病理研究会
    • Related Report
      2022 Research-status Report

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Published: 2022-09-01   Modified: 2025-01-30  

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