Molecular mechanism of regulation of PSM activity by NRF1 O-GlcNAc modification

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08618
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: Sekine Hiroki 東北大学, 加齢医学研究所, 助教 (50506285)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 転写因子 / プロテアソーム / タンパク質恒常性 / 翻訳後修飾

Outline of Final Research Achievements

Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1). O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究でO-GlcNAc化ががんにおいて、プロテアソーム活性維持に関わることを明らかとした。一方で細胞内のタンパク質の恒常性維持（プロテオスタシス）は、正常な細胞機能にとっても極めて重要であり、その破綻が神経変性疾患、老化現象など多くの疾患の分子基盤となることが明らかにされている。またO-GlcNAc化は細胞の栄養状態によって制御されており、神経機能維持、日周性維持など多くの生命現象に関与する。本研究で明らかとしたO-GlcNAc化-プロテアソーム活性という軸は、これら幅広い生命現象に関わる可能性があり、がんだけでなく他の分野への波及効果は大きいと考えられる。