Elucidation of the molecular mechanism of cancer growth signaling by protein O-GlcNAcylation

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07609
• 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: The University of Tokyo
• Principal Investigator: Kubota Yuji 東京大学, 医科学研究所, 講師 (70614973)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: O-GlcNAc / MAPK / がん

Outline of Final Research Achievements

Protein O-GlcNAcylation is a reaction that a single GlcNAc molecule (a glucose metabolite) is conjugated to a protein. In this study, I identified the modification site of a novel O-GlcNAcylated protein and found that this modification contributes to the activation of the MAPK pathway, which regulates cell proliferation. Furthermore, I found that an increase in the O-GlcNAc modification of this molecule alters its interaction with a regulatory molecules of the MAPK pathway and thereby enhances a proliferative signal. Furthermore, in cancer cells, in coincidence with increased glucose uptake and metabolism, O-GlcNAcylation of this molecule is also enhanced, thus promoting the abnormal activation of MAPK signaling and proliferative potential.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

癌細胞ではグルコース取り込みと代謝促進により（Warburg効果）、様々な癌悪性形質が惹起されている。グルコース代謝産物であるUDP-GlcNAcも同様に癌で増進しており、蛋白質O-GlcNAc化のドナーとして本修飾反応を促進するが、発癌への寄与は不明な点が多い。本研究の結果、Warburg効果によるグルコース代謝増進を癌増殖シグナルへと変換する、新たな仕組みを発見した。こうした「O-GlcNAc異常」と「細胞増殖制御」を分子レベルでリンクした知見は、様々な生理プロセスのみならず、癌をはじめとする重篤な疾患発症（糖尿病、神経変性疾患）の機序解明や治療法開発に重要な考察を与えると期待される。