Alteration of epigenome in seletecd genomic regions against gastrointestinal cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K19553
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Chiba University
• Principal Investigator: Kaneda Atsushi 千葉大学, 大学院医学研究院, 教授 (10313024)
• Project Period (FY): 2022-06-30 – 2024-03-31
• Keywords: がん / エピジェネティクス

Outline of Final Research Achievements

Cell fate e.g. development or differentiation is determined by epigenome, and its abnormalities cause various diseases. In this study, important epigenomic aberrations in gastric cancer are analyzed using clinical gastric cancer specimens and cell culture models, to elucidate molecular mechanisms for gastric cancer development such as enhancer activation by transcription factors and loop formation. Aberrations of epigenome and 3D interactome due to environmental factors such as viral infection were also elucidated. We identified important epigenomic aberrations, sequence characteristics of the target regions, and activating mechanisms. New condensate compounds using PI polyamide were synthesized so that an epigenomic enzyme inhibitor could be preferentially recruited to genomic regions with specific nucleotide sequence characteristics, to conduct region-selective intervention of epigenomic modification and lay the foundation for the development of anticancer compounds.

Free Research Field

消化器癌

Academic Significance and Societal Importance of the Research Achievements

癌に対しゲノム変異を応用した標的薬剤開発やがんゲノム医療が進められている中で、もう一つの重要なドライバー分子異常であるエピゲノム異常に対する治療開発は遅れている。本研究では胃癌や、ウイルス感染など発癌性のエピゲノム異常を誘導する環境要因に焦点を当て、発癌に重要なエンハンサー領域のエピゲノム異常や３Dクロマチン構想変化、その原因となる転写因子や外来ウイルスDNAの結合など、癌発生に重要なエピゲノム変化を同定した。それら特定の塩基配列的特徴を持ったゲノム領域に、エピゲノム酵素阻害薬を誘導できるようにPIポリアミドとの縮合化合物を合成し、選択的エピゲノム改変による新たな抗癌剤開発の基盤を築いた。