Reprogramming of metabolic networks in COP1-mediated oncogenesis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07387
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cell biology
• 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, 博士研究員 (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) ; 横山 隆志 奈良先端科学技術大学院大学, 先端科学技術研究科, 助教 (00535833)
• Project Period (FY): 2017-04-01 – 2020-03-31
• 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 metabolism for degradation. We aimed how cancer-initiating cells acquire a specific energy metabolic system essential for their proliferation in the process of cellular transformation by investigating the COP1’s activities linking both tumorigenesis and metabolism.
Several important results were obtained in this study. The Trib1-COP1 ligase complex targets a group of the metabolic enzymes including ACC as well as C/EBPalpha, a transcription factor regulating myeloid differentiation, for degradation during myeloid leukemogenesis. The stable expression of an ACC mutant, which was resistant to degradation, suppressed Trib1-COP1-induced growth-promoting activity in a primary bone marrow culture and delayed the onset of acute myeloid leukemia (AML) in mouse models. The up-regulated expression of these enzymatic factors has potential as a strategy for cancer therapy.

Free Research Field

生物学

Academic Significance and Societal Importance of the Research Achievements

近年、がんと代謝の研究は新たな治療戦略の開発の必要性の面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。