Efficient identification of low-frequency gene mutations that favor cancer growth

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06560
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: HINO Nobumasa 大阪大学, 大学院薬学研究科, 講師 (90469916)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: がんゲノム / タンパク質立体構造 / タンパク質間相互作用 / クロスリンク / 人工アミノ酸 / KEAP1

Outline of Final Research Achievements

The relationship between aberrant protein-protein interactions caused by low-frequency cancer mutations and cellular functions was investigated, with the objective of identifying low-frequency mutations that favor cancer growth. It was demonstrated that low-frequency cancer mutations on the surface of KEAP1 protein found in cancer patients attenuate its interaction with Rab8a. However, stable expression of the KEAP1 mutant did not significantly affect cell proliferation and tumor growth. On the other hand, suppression of KEAP1 expression enhanced proliferation of cancer cell lines, and this enhancement was canceled by suppression of Rab8a expression. These results suggest that KEAP1 suppresses Rab8a's ability to promote cell proliferation, but that the weakening of its interaction with Rab8a by the KEAP1 point mutation is not significant enough to affect cell proliferation.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

がんゲノム変異大部分を占める低頻度変異とがんとの関連を明らかにする戦略は確立されておらず、新たな治療標的の探索は進んでいない。我々は、独自手法によりがん低頻度変異により異常をきたすKEAP1-Rab8a間相互作用を同定した。KEAP1点変異による細胞増殖や腫瘍生育への影響はみられなかったものの、KEAP1がRab8aの腫瘍増殖促進を抑制する結果が得られた。本結果は、KEAP1とRab8aが属するそれぞれの蛋白質間相互作用ネットワークのクロストークを示すものであり、KEAP1の発現低下が見られるがんに対して、Rab8aもしくはその下流の因子が新たな治療標的となる可能性を示している。