Reprogramming of ACC lipid metabolic pathways in COP1-mediated oncogenesis

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06626
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Nara Institute of Science and Technology
• Principal Investigator: Kato Noriko 奈良先端科学技術大学院大学, 先端科学技術研究科, 特任准教授 (10252785)
• Co-Investigator(Kenkyū-buntansha): 加藤 順也 奈良先端科学技術大学院大学, 先端科学技術研究科, 教授 (00273839)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 細胞増殖分化 / 発がん / エネルギー代謝

Outline of Final Research Achievements

An E3 ubiquitin ligase COP1 targets several factors that are involved in tumorigenesis and energy metabolism for degradation. We identified fatty acid synthesis enzymes acetyl-CoA carboxylase (ACC) as a target of the COP1-Trib1 ligase complex and investigated how cancer-initiating cells acquire a specific energy metabolic system essential for their proliferation in the process of cellular transformation with leukemic mouse models.
The COP1-Trib1 complex-mediated ACC1 degradation results in an excessive supply of cellular energy, which is utilized to reduce ROS levels for cell survival and differentiation block in leukemia-initiating cells. An ACC1 mutant resistant to degradation inhibited the COP1-Trib1-driven cell growth and promoted the terminal differentiation, thereby suppressing myeloid leukemia development. The upregulated expression of these enzymatic factors has potential as a strategy for cancer therapy.

Free Research Field

腫瘍細胞生物学

Academic Significance and Societal Importance of the Research Achievements

がんと代謝の研究は新たな治療戦略の開発の必要性から活発に行われている。COP1は発がん・代謝の両経路に関わり、分解標的となる造血系転写因子・脂質代謝酵素群を安定化すると、がん化は抑制される。このことは、COP1研究は発がんと代謝の相互作用の研究モデルとして優れており、発がん過程における代謝ネットワークのリプログラミング機構のより深い理解をもたらし、新規がん治療薬の開発に貢献できる。