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The biological significance of the diversity of the epithelial cell integrity

Research Project

Project/Area Number 18H02608
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionHokkaido University

Principal Investigator

Sabe Hisataka  北海道大学, 医学研究院, 教授 (40187282)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Keywords上皮性維持 / p53 / CDH1 / ヒストン修飾 / 代謝変換 / 免疫監視 / 免疫回避 / EMT / ヒストン / 上皮細胞 / p53
Outline of Final Research Achievements

In this study, we aimed to elucidate the biological significance of the p53-dependent or -independent epithelial integrity, in which p53 ensures the E-cadherin expression by directly binding to the CDH1 locus. Especially, we aimed to determine whether or not p53 bonds to the CDH1 locus in normal epithelial cells or in the in vivo settings, or the binding activity manifests only when the cells are immortalized or transformed. We studied factors that affect the p53-dependency when cells maintain the epithelial integrity by RNA-Seq, ChIP-Seq and metabolome analyses. We found that butyric acid elevates acetylated histones at the CDH1 locus, facilitating the p53-binding to this site. Therefore, we found that the metabolic status of the cell is critical for the p53-dependent epithelial integrity.

Academic Significance and Societal Importance of the Research Achievements

今回発見したp53の機能は、p53がE-カドヘリン遺伝子の発現調節部位に結合し、ヒストン修飾を制御する。また、高濃度酪酸などによるヒストン修飾の揺らぎがゲノムDNAへのp53結合性に影響することが分かった。酪酸は消化管から吸収され、β酸化によりアセチルCoAに分解され、クエン酸回路によりエネルギー源として利用される。本成果が生体に普遍的なものであるならば、がんの悪性度進展だけではなく、iPS技術などを用いる再生医療においても深く考慮されるべき、未知の分子メカニズムが存在することになる。また、上皮性と免疫監視とが関連することも明らかにし、癌免疫治療の発展に寄与する根幹的知見を得た。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (14 results)

All 2021 2020 2019 2018 Other

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (7 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Inhibition of mutant KRAS-driven overexpression of ARF6 and MYC by an eIF4A inhibitor drug improves the effects of anti-PD-1 immunotherapy for pancreatic cancer2021

    • Author(s)
      橋本あり,半田 悠,畑宗一郎,蔦保暁生,吉田隆雄,平野 聡,橋本 茂,佐邊壽孝
    • Journal Title

      Cell Communication and Signaling

      Volume: in press

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High expression of AMAP1, an ARF6 effector, is associated with elevated levels of PD-L1 and fibrosis of pancreatic cancer.2020

    • Author(s)
      Tsutaho, A., Hashimoto, A., Hashimoto, S., Hata, S., Kachi, S., Hirano, S., and Sabe, H.
    • Journal Title

      Cell Communication and Signaling

      Volume: 18(1) Issue: 1 Pages: 101-101

    • DOI

      10.1186/s12964-020-00608-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics and immune evasion of pancreatic cancer2019

    • Author(s)
      Hashimoto, S*., Furukawa, S*., Hashimoto, A*., Tsutaho, A., Fukao, A., Sakamura, Y., Parajuli, G., Onodera, Y., Otsuka, Y., Handa, H., Oikawa, T., Hata, S., Nishikawa Y., Mizukami, Y., Kodama, Y., Murakami M., Fujiwara, T., Hirano, S., and Sabe, H. (*Equally contributed)
    • Journal Title

      Proceedings of the National Academy of the Sciences of the United States of America

      Volume: 116 Issue: 35 Pages: 17450-17459

    • DOI

      10.1073/pnas.1901765116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection2019

    • Author(s)
      Nishikawa Shigeto、Menju Toshi、Takahashi Koji、Miyata Ryo、Chen Yoshikawa Toyofumi Fengshi、Sonobe Makoto、Yoshizawa Akihiko、Sabe Hisataka、Sato Tosiya、Date Hiroshi
    • Journal Title

      Cancer Management and Research

      Volume: Volume 11 Pages: 3419-3432

    • DOI

      10.2147/cmar.s200819

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] p53-Dependent and -Independent Epithelial Integrity: Beyond miRNAs and Metabolic Fluctuations.2018

    • Author(s)
      Oikawa T, Otsuka Y, Sabe H.
    • Journal Title

      Cancers

      Volume: 10(6) Issue: 6 Pages: 162-162

    • DOI

      10.3390/cancers10060162

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epithelial-specific histone modification of the miR-96/182 locus targeting AMAP1 mRNA predisposes p53 to suppress cell invasion in epithelial cells.2018

    • Author(s)
      Handa, H*., Hashimoto, A*., Hashimoto S., Sugino, S., Oikawa, T., and Sabe, H.
    • Journal Title

      Cell Commun. Signal.

      Volume: 16(1) Issue: 1 Pages: 94-94

    • DOI

      10.1186/s12964-018-0302-6

    • NAID

      120006585787

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Pancreatic KRAS/TP53 oncogenes promote immune evasion via activating eIF4A/4E-dependent translation and protein prenylation2019

    • Author(s)
      Hisataka Sabe
    • Organizer
      The 38th Sapporo International Cancer Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] p53 excludes EZH2 from H3.1 interactome during S phase to maintain histone code.2019

    • Author(s)
      Oikawa T, Ohnishi N, Onodera Y, Hashimoto A, Ueda K, Sabe H
    • Organizer
      The 38th Sapporo International Cancer Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Requirement for p53 in intra-nuclear dynamics of the K27-trimethylated histone H3 during DNA replication.2019

    • Author(s)
      Tsukasa Oikawa, Naomi Ohnishi, Yasuhito Onodera, Ari Hashimoto, Koji Ueda and Hisataka Sabe
    • Organizer
      第92回日本生化学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Upregulation of eIF4A/4E-dependent mRNA translation is the major target of KRAS signaling.2019

    • Author(s)
      Hashimoto A, Hashimoto S, Furukawa S, Tsutaho A, Fukao A, Onodera Y, Handa H, Oikawa T, Hata S, Nishikawa Y, Mizukami Y, Kodama Y, Murakami M, Fujiwara T, Hirano S, and Sabe H.
    • Organizer
      第19回蛋白質科学・第71回日本細胞生物合同年次大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Pancreatic KRAS/TP53 mutations promote ARF6-based immune evasion via activating mRNA translation and protein prenylation.2019

    • Author(s)
      Hashimoto A, Hashimoto S, Furukawa S, Tsutaho A, Fukao A, Onodera Y, Handa H, Oikawa T, Hata S, Nishikawa Y, Mizukami Y, Kodama Y, Murakami M, Fujiwara T, Hirano S, and Sabe H.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Requirement for p53 in intra-nuclear dynamics of the K27-trimethylated histone H3 during DNA replication2018

    • Author(s)
      Tsukasa Oikawa, Yuki Shino, Suguru Kurosawa, Yasuhito Onodera, Yutaro Otsuka, Ari Hashimoto, Hisataka Sabe
    • Organizer
      第70回日本細胞生物学会(日本発生生物学会合同大会)
    • Related Report
      2018 Annual Research Report
  • [Presentation] Epithelial-mesenchymal transition accompanies mitochondrial fission and enhanced OXPHOS activity2018

    • Author(s)
      Haruka Handa, Shingo Takada, Yutaro Otsuka, Yasuhito Onodera, Tsukasa Oikawa, Hisataka Sabe
    • Organizer
      Nutrient Signaling 2018 Cold Spring Harbor Laboratory meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 研究室ホームページ

    • URL

      http://g21001.med.hokudai.ac.jp/

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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