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

2020 Fiscal Year Final Research Report

• 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
• Keywords: 低酸素 / Hypoxia / DEC1 / DEC2

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.

Free Research Field

外科系歯学

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。