Development of anticancer drugs based on the knowledge of the roles of Ftsj1-mediated tRNA modification

• Project/Area Number: 16K18989
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Okayama University (2017); Kumamoto University (2016)
• Principal Investigator: Fujimura Atsushi 岡山大学, 医歯薬学総合研究科, 助教 (10771082)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: tRNA修飾酵素 / 癌幹細胞 / 低分子化合物スクリーニング / 翻訳メカニズム / tRNA修飾 / 薬剤開発 / 癌転移・浸潤 / Hippo経路 / 創薬

Outline of Final Research Achievements

To elucidate the roles of translational machinery in cancer biology, I focused on tRNA-modification enzyme FTSJ1, and investigated how FTSJ1 determined the cancer cell fate. FTSJ1 is required to sustain the cancer stem cell-related traits: when FTSJ1 is down-regulated, the cancer cells lost the self-renewal capacity and tumor-forming capacity. As a functional target of FTSJ1, I identified Cyr61 and CTGF, both of which are essential to control cancer stem cell. These results indicate the possibilities of the development of FTSJ1 inhibitor as a groundbreaking anti-cancer drug.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、がん生物学において近年勃興しつつある「転写と翻訳の乖離」の問題解決の一端を担うものと考える。とりわけ、「転写と翻訳の乖離」に起因する「がん組織の不均一性」に関しては、がんを難治たらしめる「幹細胞性」の獲得・維持と密接に関係しているため、本研究で明らかになった事項を外挿すれば、「がん幹細胞を標的とする抗がん剤の開発」といった、全く新しい切り口からの制癌戦略の構築が可能となる。このことは、本研究成果が学術的に意義深いものだけでなく、がん治療法の開発といった社会的意義にも大きく影響を与えるものであると確信する。

Research Products

• [Journal Article] Defective Mitochondrial tRNA Taurine Modification Activates Global Proteostress and Leads to Mitochondrial Disease. (2018)
  • Author(s): Fakruddin M, Wei FY, Suzuki T, Asano K, Kaieda T, Omori A, Izumi R, Fujimura A, Kaitsuka T, Miyata K, Araki K, Oike Y, Scorrano L, Suzuki T, Tomizawa K.
  • Journal Title: Cell Rep. Volume: 22 Issue: 2 Pages: 482-496
  • DOI: 10.1016/j.celrep.2017.12.051
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion. (2017)
  • Author(s): Takahashi N, Wei FY, Watanabe S, Hirayama M, Ohuchi Y, Fujimura A, Kaitsuka T, Ishii I, Sawa T, Nakayama H, Akaike T, Tomizawa K.
  • Journal Title: Nucleic Acids Res. Volume: 45 Issue: 1 Pages: 435-445
  • DOI: 10.1093/nar/gkw745
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mtu1-mediated thiouridine formation of mitochondrial tRNAs is required for mitochondrial translation and is involved in reversible infantile liver injury (2016)
  • Author(s): Wu, Y., Wei, F. Y., Kawarada, L., Suzuki, T., Araki, K., Komohara, Y., Fujimura, A., Kaitsuka, T., Takeya, M., Oike, Y., Suzuki, T., Tomizawa, K.
  • Journal Title: PLoS genetics Volume: 12 Issue: 9 Pages: e1006355-e1006355
  • DOI: 10.1371/journal.pgen.1006355
  • Peer Reviewed / Open Access
• [Journal Article] HDAC9 regulates the alternative lengthening of telomere (ALT) pathway via the formation of ALT-associated PML bodies. (2016)
  • Author(s): Mohd. Raeed Jamiruddin, Taku Kaitsuka, Farzana Hakim, Atsushi Fujimura, Fan-Yan Wei, Hisato Saitoh, Kazuhito Tomizawa
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 481 Issue: 1-2 Pages: 25-30
  • DOI: 10.1016/j.bbrc.2016.11.026
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Lineage-restricted dedifferentiation of neurons by transient expression of YAP-TAZ (2018)
  • Author(s): 藤村篤史
  • Organizer: 第95回日本生理学会大会
• [Presentation] FTSJ1依存性翻訳機構による転写因子ネットワーク維持は悪性脳腫瘍幹細胞に必須である (2017)
  • Author(s): 藤村篤史、山村遼介、山本隆広、魏范研、貝塚拓、富澤一仁
  • Organizer: 第９４回日本生理学会大会
  • Place of Presentation: 静岡県浜松市
  • Year and Date: 2017-03-28
• [Presentation] tRNA修飾酵素FTSJ1による癌進展制御機構 (2017)
  • Author(s): 山村遼介、藤村篤史、永芳友、魏范研、貝塚拓、富澤一仁
  • Organizer: 第９４回日本生理学会大会
  • Place of Presentation: 静岡県浜松市
  • Year and Date: 2017-03-28
• [Presentation] 修飾ヌクレオチドの排出機構 (2017)
  • Author(s): 森岡太意気、魏范研、藤村篤史、富澤一仁
  • Organizer: 第９４回日本生理学会大会
  • Place of Presentation: 静岡県浜松市
  • Year and Date: 2017-03-28
• [Presentation] Ftsj1 determines cancer stem cell-related traits of breast and gastric cancer (2016)
  • Author(s): Atsushi Fujimura, Ryosuke Yamamura, Yu Nagayoshi, Fan-Yan Wei, Taku Kaitsuka, Kazuhito Tomizawa
  • Organizer: tRNA 26th Conference
  • Place of Presentation: Jeju, South Korea
  • Year and Date: 2016-09-04
  • Int'l Joint Research