Investigation of molecular mechanisms to drive oncogene expression

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07568
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa University
• Principal Investigator: Hazawa Masaharu 金沢大学, 新学術創成研究機構, 准教授 (40622460)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: nucleus / nuclear transport / gene regulation / genomic function / phase separation / super enhancer / squamous cell carcinoma

Outline of Final Research Achievements

This study aimed to elucidate the mechanisms by which the expression of the squamous cell carcinoma-specific master transcription factor TP63 is induced and maintained, focusing on the genomic structure and functional environment associated with nuclear architecture. The super-enhancers (SEs) that induce the expression of TP63 were visualized using DNA-FISH method, and their localization within the nuclear space was analyzed. It was revealed that several SEs, including TP63, localize near the nuclear pore. This localization was found to involve molecular interactions between SE component proteins and nuclear pore complex constituents. A method was devised to biochemically detect these molecular interactions, and by combining it with MS analysis, a comprehensive profiling of SE components and nuclear pore interaction factors was achieved.

Free Research Field

Cancer cell biology

Academic Significance and Societal Importance of the Research Achievements

本研究により、細胞の重要な機能発現に関わるマスター転写因子の発現量は、核構造と結びついた分子基盤により保証されていることが明らかとなった。とりわけ、ゲノムの空間的な配置に関わる分子基盤の一面が明らかとなり、これらを操作する低分子化合物開発がすすむことで、目的とする細胞分化誘導技術の創成やがん治療戦略につながることが期待される。
また、近年注目される相分離現象に関与するタンパク質の網羅的な解析技術基盤の開発にも成功し、この技術は核内相分離によるゲノムトポロジー形成機序の解明に役立ち、生命科学の発展に貢献することが期待できる。