GTP Metabolism in Epithelial-Mesenchymal Transition

• Project/Area Number: 17KK0199
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Osaka University (2020-2022); Keio University (2017-2019)
• Principal Investigator: Tabata Sho 大阪大学, 蛋白質研究所, 特任講師(常勤) (30708342)
• Project Period (FY): 2018 – 2022
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
• Keywords: 上皮間葉転換 / 代謝 / メタボローム解析 / 核酸代謝 / メタボローム / GTP

Outline of Final Research Achievements

Epithelial-mesenchymal transition (EMT) is involved in distant metastasis and drug resistance of cancer. Although TGF-β-dependent signal transduction and transcription factors for EMT have been identified, how intracellular metabolism is involved in EMT remains to be fully elucidated. In this study, combined metabolome and transcriptome analysis revealed that unique amino acid and nucleic acid metabolisms contribute to the promotion of EMT. We also found that elevated expression of prolyl 4-hydroxylase α3 (P4HA3), an amino acid metabolic enzyme, and CTP synthase (CPTS), a pyrimidine nucleic acid metabolic enzyme, are important for the induction of EMT. These results suggest that inhibitors of both enzymes may be therapeutic agents for cancer.

Academic Significance and Societal Importance of the Research Achievements

がんにおけるEMT は10 年以上前から精力的に研究されており、EMTに関連する遺伝子の転写因子制御、翻訳機構、非コードRNAの制御、選択的スプライシングやタンパク質安定性など、様々な分子機構が明らかになっている。しかしながら、EMT特異的な代謝変化およびその機構については不明な点が多い。本研究で、EMTにおける特異的なアミノ酸および核酸の代謝変化が示され、EMTの新しい分子基盤が明らかになった。また、がんEMTおいてアミノ酸代謝酵素のP4HA3および、ピリミジン代謝酵素のCTPSの発現上昇が、重要であることが判明し、その両酵素の阻害剤は新規がん治療薬になる可能性がある。

Research Products

• [Int'l Joint Research] シンシナティ大学(米国) (2018)
  • Year and Date: 2018-10-01
• [Journal Article] L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis (2023)
  • Author(s): Tabata Sho、Kojima Yasushi、Sakamoto Takeharu、Igarashi Kaori、Umetsu Ko、Ishikawa Takamasa、Hirayama Akiyoshi、Kajino-Sakamoto Rie、Sakamoto Naoya、Yasumoto Ken-ichi、Okano Keiichi、Suzuki Yasuyuki、Yachida Shinichi、Aoki Masahiro、Soga Tomoyoshi
  • Journal Title: Oncogene Volume: 42 Issue: 16 Pages: 1294-1307
  • DOI: 10.1038/s41388-023-02632-7
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomics of small extracellular vesicles derived from isocitrate dehydrogenase 1-mutant HCT116 cells collected by semi-automated size exclusion chromatography (2023)
  • Author(s): Hayasaka Ryosuke、Tabata Sho、Hasebe Masako、Ikeda Satsuki、Hikita Tomoya、Oneyama Chitose、Yoshitake Jun、Onoshima Daisuke、Takahashi Kumiko、Shibata Takahiro、Uchida Koji、Baba Yoshinobu、Soga Tomoyoshi、Tomita Masaru、Hirayama Akiyoshi
  • Journal Title: Frontiers in Molecular Biosciences Volume: 9 Pages: 1049402-1049402
  • DOI: 10.3389/fmolb.2022.1049402
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic reprograming of cancer as a therapeutic target. (2022)
  • Author(s): Furukawa T, Tabata S, Minami K, Yamamoto M, Kawahara K, Tanimoto A
  • Journal Title: Biochim Biophys Acta Gen Subj Volume: 1867 Issue: 3 Pages: 130301-130301
  • DOI: 10.1016/j.bbagen.2022.130301
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reprogramming of glutamine metabolism via glutamine synthetase silencing induces cisplatin resistance in A2780 ovarian cancer cells (2021)
  • Author(s): Guo Jing、Satoh Kiyotoshi、Tabata Sho、Mori Masaru、Tomita Masaru、Soga Tomoyoshi
  • Journal Title: BMC Cancer Volume: 21 Issue: 1 Pages: 174-174
  • DOI: 10.1186/s12885-021-07879-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell Shape‐Based Chemical Screening Reveals an Epigenetic Network Mediated by Focal Adhesions (2021)
  • Author(s): Kanazawa Tomomi、Michida Hiroki、Uchino Yuki、Ishihara Akari、Zhang Suxiang、Tabata Sho、Suzuki Yutaka、Imamoto Akira、Okada Mariko
  • Journal Title: The FEBS Journal Volume: - Issue: 19 Pages: 5613-5628
  • DOI: 10.1111/febs.15840
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methionine restriction breaks obligatory coupling of cell proliferation and death by an oncogene Src in Drosophila (2021)
  • Author(s): Nishida Hiroshi、Okada Morihiro、Yang Lynna、Takano Tomomi、Tabata Sho、Soga Tomoyoshi、Ho Diana M、Chung Jongkyeong、Minami Yasuhiro、Yoo Sa Kan
  • Journal Title: eLife Volume: 10
  • DOI: 10.7554/elife.59809
  • NAID: 120007033553
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomic Analysis of Small Extracellular Vesicles Derived from Pancreatic Cancer Cells Cultured under Normoxia and Hypoxia (2021)
  • Author(s): Hayasaka Ryosuke、Tabata Sho、Hasebe Masako、Ikeda Satsuki、Ohnuma Sumiko、Mori Masaru、Soga Tomoyoshi、Tomita Masaru、Hirayama Akiyoshi
  • Journal Title: Metabolites Volume: 11 Issue: 4 Pages: 215-215
  • DOI: 10.3390/metabo11040215
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β-dependent reprogramming of amino acid metabolism induces epithelial?mesenchymal transition in non-small cell lung cancers (2021)
  • Author(s): Nakasuka Fumie, Tabata Sho, Sakamoto Takeharu, Hirayama Akiyoshi, Ebi Hiromichi, Yamada Tadaaki, Umetsu Ko, Ohishi Maki, Ueno Ayano, Goto Hisatsugu, Sugimoto Masahiro, Nishioka Yasuhiko, Yamada Yasuhiro, Tomita Masaru, Sasaki Atsuo T, Yano Seiji, Soga Tomoyoshi
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s42003-021-02323-7
  • NAID: 120007178465
  • Peer Reviewed / Open Access
• [Journal Article] The use of a double coaxial electrospray ionization sprayer improves the peak resolutions of anionic metabolites in capillary ion chromatography-mass spectrometry. (2020)
  • Author(s): Hirayama A, Tabata S, Kudo R, Hasebe M, Suzuki K, Tomita M, Soga T.
  • Journal Title: J Chromatogr A Volume: - Pages: 460914-460914
  • DOI: 10.1016/j.chroma.2020.460914
  • Peer Reviewed