The biological significance of the diversity of the epithelial cell integrity

• Project/Area Number: 18H02608
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Hokkaido 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: ¥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。

Research Products

• [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 cancer (2021)
  • 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
  • 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
  • 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 cancer (2019)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection (2019)
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Pancreatic KRAS/TP53 oncogenes promote immune evasion via activating eIF4A/4E-dependent translation and protein prenylation (2019)
  • Author(s): Hisataka Sabe
  • Organizer: The 38th Sapporo International Cancer Symposium
  • 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
  • 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
• [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
• [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
• [Presentation] Requirement for p53 in intra-nuclear dynamics of the K27-trimethylated histone H3 during DNA replication (2018)
  • 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）
• [Presentation] Epithelial-mesenchymal transition accompanies mitochondrial fission and enhanced OXPHOS activity (2018)
  • Author(s): Haruka Handa, Shingo Takada, Yutaro Otsuka, Yasuhito Onodera, Tsukasa Oikawa, Hisataka Sabe
  • Organizer: Nutrient Signaling 2018 Cold Spring Harbor Laboratory meeting
  • Int'l Joint Research
• [Remarks] 研究室ホームページ
  • URL: http://g21001.med.hokudai.ac.jp/