Development of novel diagnosis and therapy in cancer targetting reversible system of intracellular glycosylation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07762
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Osaka Medical and Pharmaceutical University
• Principal Investigator: Toshihisa Takeuchi 大阪医科薬科大学, 医学部, 准教授 (30445986)
• Co-Investigator(Kenkyū-buntansha): 森脇 一将 大阪医科薬科大学, 医学部, 講師 (00467656)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: O-GlcNAc修飾 / FOXM1 / FBXL2

Outline of Final Research Achievements

O-GlcNAcylation mediates translational modification through glucose metabolite and is upregulated in cancer cells to promote cancer progression. Many of its target molecules are known and the diverse functions are not fully understood. In this study, we showed that elevated O-GlcNAcylation upregulates expression levels of FOXM1, which is a critical oncogenic transcription factor and its overexpression is associated with poor prognosis of various cancers, via decrease of its ubiquitination. In NUGC-3 human gastric cancer cells, elevated O-GlcNAcylation by OGA (O-GlcNAcase) inhibitor promoted cell proliferation and resistance to some anticancerdrugs. On the contrary, downregulated O-GlcNAcylation by OGT (O-GlcNAc transferase) inhibitor reduced cell proliferation and increased sensitivity to them. These data indicate that elevated O-GlcNAcylation promotes cancer cell proliferation and drug resistance via upregulation of FOXM1, and OGT and FOXM1 are potential targets for cancer therapy.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

癌で上昇するO-GlcNAc修飾は、癌の治療標的として期待されてきたが、O-GlcNAcの標的分子が多岐に渡り、その機能の全容は分かっていなかった。本研究により、O-GlcNAc修飾が、癌の予後不良マーカーとして注目されているFOXM1の発現を制御して癌の進展に強く影響していること、また、抗腫瘍薬の効果をも左右していることが明らかになった。これらの結果は、癌の特性を知り、新しい癌治療の可能性を追求する上で役立つものと期待される。