Development of a molecular targeting anti-cancer therapy against hypoxia inducible DEC transcription factors

• Project/Area Number: 18K09768
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Hiroshima University
• Principal Investigator: Tanimoto Keiji 広島大学, 原爆放射線医科学研究所, 准教授 (90335688)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 低酸素 / Hypoxia / DEC1 / DEC2 / 低酸素応答 / 転写因子 / 転写制御 / hypoxia / DEC / 分子標的治療

Outline of Final Research Achievements

In this study, we investigated the potential of transcription factors DEC1 and DEC2, that are induced under hypoxia and regulate DNA damage response and apoptosis, as anticancer molecular targets for treatment-resistant oral cancers. We so far established the reporter-based screening system using DEC-responsive sequences identified and analyzed in DNA damage response genes repressed by DEC1 and DEC2. On the other hand, the evaluation of cell proliferation by siRNA-based DEC1 and DEC2 inhibition showed that DEC2 inhibition was more effective to inhibit cancer cell proliferation under both normoxic and hypoxic conditions. Furthermore, we found that AURKB gene expression was greatly reduced with low-dose-rate irradiation, suggesting that DEC2 may be involved in the suppression. In addition, we found that decreased expression of the AURKB gene might be involved in modification of anticancer drug sensitivity, suggesting a novel therapeutic strategy.

Academic Significance and Societal Importance of the Research Achievements

本申請研究では，新しい抗がん戦略として，がんの特徴である低酸素環境で働く転写因子DEC1およびDEC2を分子標的とした治療が有用であるか検討するとともに，その分子機構の解明に取り組んだ。さまざまな試みの中で，DEC2を阻害するとがん細胞の増殖を効率良く抑制できることが明らかとなった。さらに，低線量率放射線照射により，DEC2によりAURKB遺伝子発現が抑制され，抗がん剤感受性が変化することを見出し，より安全で効果的な新しい治療プロトコールへの応用展開が期待された。

Research Products

• [Journal Article] GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A. (2020)
  • Author(s): Kazumi Shimamoto, Keiji Tanimoto*, Takahiro Fukazawa, Hideaki Nakamura, Akinori Kanai, Hidemasa Bono, Hiromasa Ono, Hidetaka Eguchi, Nobuyuki Hirohashi
  • Journal Title: Carcinogenesis Volume: inpress Issue: 9 Pages: 1184-1194
  • DOI: 10.1093/carcin/bgaa010
  • Peer Reviewed
• [Journal Article] がんにおける低酸素応答性転写因子HIF (2020)
  • Author(s): 谷本圭司
  • Journal Title: 医学のあゆみ Volume: 274 Pages: 265-270
• [Journal Article] Simulated microgravity enhances CDDP-induced apoptosis signal via p53-independent mechanisms in cancer cells. (2019)
  • Author(s): Takahiro Fukazawa, Keiji Tanimoto*, Looniva Shrestha, Takeshi Imura, Shinya Takahashi, Taijiro Sueda, Nobuyuki Hirohashi, Eiso Hiyama, Louis Yuge
  • Journal Title: PLOS ONE Volume: 14 Issue: 7 Pages: 1-14
  • DOI: 10.1371/journal.pone.0219363
  • Peer Reviewed / Open Access
• [Journal Article] Simulated microgravity attenuates myogenic differentiation via epigenetic regulations (2018)
  • Author(s): Takuma Furukawa, Keiji Tanimoto, Takahiro Fukazawa, Takeshi Imura, Yumi Kawahara, Louis Yuge
  • Journal Title: Npj Microgravity Volume: 4 Issue: 1
  • DOI: 10.1038/s41526-018-0045-0
  • Peer Reviewed / Open Access
• [Presentation] 低線量率放射線および低酸素刺激により変動する遺伝子群 (2020)
  • Author(s): 島袋紀一，谷本圭司，柿本直也，廣橋伸之
  • Organizer: 第45回中国放射線影響研究会
• [Presentation] The effects of low-dose irradiation on the hypoxic cells (2020)
  • Author(s): Kiichi Shimabukuro, Keiji Tanimoto, Naoya Kakimoto, Nobuyuki Hirohashi
  • Organizer: The 4th International Symposium of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science
  • Int'l Joint Research
• [Presentation] The effects of low-dose irradiation on the hypoxic cells. (2020)
  • Author(s): Kiichi Shimabukuro, Keiji Tanimoto, Naoya Kakimoto, Nobuyuki Hirohashi
  • Organizer: The 4th International Symposium of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science
• [Presentation] 低酸素がん細胞におけるビスフォスフォネート製剤の抗腫瘍分子機構． (2019)
  • Author(s): 光野 萌，谷本圭司，島袋紀一，島本和美，廣橋伸之
  • Organizer: 第60回原子爆弾後障害癌研究会
• [Presentation] 新規低酸素誘導性転写因子GLIS1の機能解析． (2019)
  • Author(s): 島本和美，谷本圭司，深澤賢宏，島袋紀一，廣橋伸之
  • Organizer: 第44回中国放射線影響研究会
• [Presentation] Significant roles of the novel hypoxia-inducible transcription factor, GLIS1, in breast cancer (2019)
  • Author(s): Keiji Tanimoto, Kazumi Shimamoto, Nobuyuki Hirohashi
  • Organizer: The 3rd International Symposium of the Network-type Joint Usage/Research Center for Radio Disaster Medical Science
  • Int'l Joint Research
• [Presentation] 新規低酸素誘導性転写因子GLIS1のがん細胞における意義 (2018)
  • Author(s): 谷本圭司，島本和美，島袋紀一，小田千代，廣橋伸之
  • Organizer: 第61回日本放射線影響学会
• [Presentation] 低酸素シグナルと放射線応答 (2018)
  • Author(s): 谷本圭司，島本和美，小田千代，廣橋伸之
  • Organizer: 第59回原子爆弾後障害研究会
• [Presentation] DEC plays a crucial role in DNA damage response via transcriptional regulation under hypoxic conditions (2018)
  • Author(s): Keiji Tanimoto, Hideaki Nakamura, Nobuyuki Hirohashi, Lorenz Poellinger, Eisaburo Sueoka
  • Organizer: The 14th Japan-Korea Joint Symposium on Cancer and Ageing Research
  • Int'l Joint Research