Reprogramming of metabolic networks in COP1-mediated oncogenesis

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 細胞増殖分化 / 発がん / エネルギー代謝 / 発がん機構

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.

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。

Research Products

• [Journal Article] Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression (2019)
  • Author(s): Nakamae Ikuko、Morimoto Tsumoru、Shima Hiroki、Shionyu Masafumi、Fujiki Hisayo、Yoneda-Kato Noriko、Yokoyama Takashi、Kanaya Shigehiko、Kakiuchi Kiyomi、Shirai Tsuyoshi、Meiyanto Edy、Kato Jun-ya
  • Journal Title: Molecules Volume: 24 Issue: 22 Pages: 4067-4067
  • DOI: 10.3390/molecules24224067
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence (2019)
  • Author(s): Lestari Beni、Nakamae Ikuko、Yoneda-Kato Noriko、Morimoto Tsumoru、Kanaya Shigehiko、Yokoyama Takashi、Shionyu Masafumi、Shirai Tsuyoshi、Meiyanto Edy、Kato Jun-ya
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 14867-14867
  • DOI: 10.1038/s41598-019-51244-3
  • NAID: 120006732446
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anti-proliferative and anti-metastatic potential of curcumin analog, pentagamavunon-1 (PGV-1), toward highly metastatic breast cancer cells in correlation with ROS generation. (2019)
  • Author(s): Maiyanto E, Putri H, Arum Larasati Y, Yudi Utomo R, Istighfari Jenie R, Ikawati M, Lestari B, Yoneda-Kto N, Nakamae I, Kawaichi M, Kato JY.
  • Journal Title: Adv. Pharm. Bull. Volume: 9 Issue: 3 Pages: 445-452
  • DOI: 10.15171/apb.2019.053
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. (2018)
  • Author(s): Larasati YA, Yoneda-Kato N, Nakamae I, Yokoyama T, Meiyanto E, Kato JY.
  • Journal Title: Sci. Rep. Volume: ８ Issue: 1 Pages: 2039-2039
  • DOI: 10.1038/s41598-018-20179-6
  • NAID: 120006732447
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPalpha to prevent Trib1-driven acute myeloid leukemia. (2017)
  • Author(s): Nakamae I, Kato JY, Yokoyama T, Ito H, Yoneda-Kato N
  • Journal Title: Blood Adv. Volume: 1 Issue: 20 Pages: 1682-1693
  • DOI: 10.1182/bloodadvances.2017007054
  • Peer Reviewed / Open Access
• [Presentation] ACC1 degradation via COP1-Trib1 complex induces metabolic reprogramming leading to myeloid leukemogenesis (2019)
  • Author(s): Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, and Noriko Yoneda-Kato
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] A novel curcumin analog inhibits tumorigenesis through prometaphase arrest and antioxidative interference (2019)
  • Author(s): Jun-ya Kato, Ikuko Nakamae, Takashi Yokoyama and Noriko Kato, Edy Meiyanto
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Suppression of tumor cell growth by targeting ROS metabolic enzymes. (2018)
  • Author(s): Nakamae I, Yoneda-Kato N, Yokoyama T, Meiyanto E, Kato JY.
  • Organizer: Cold Spring Harbor Laboratory Meeting, New York, USA
  • Int'l Joint Research
• [Presentation] COP1-Trib1 targets ACC1 for degradation and protects leukemic cells from metabolic stress in acute myeloid leukemia. (2018)
  • Author(s): Ito H, Nakamae I, Yokoyama T, Kato JY, Yoneda-Kato N.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Tribbles-COP1 ligase complex in acute myeloid leukemia (2018)
  • Author(s): Yoneda-Kato N, Ito H, Nakamae I, Yokoyama T, Kato JY.
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] 急性骨髄性白血病の発症過程におけるCOP1-Trib1複合体リガーゼを介したACC1蛋白質分解に伴う代謝機能異常に関する解析 (2018)
  • Author(s): 伊藤秀矩、中前伊公子、横山隆志、加藤順也、加藤規子
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Myeloid leukemia factor 1 stabilizes tumor suppressor C/EBPalpha to prevent Trib1-driven acute myeloid leukemia. (2017)
  • Author(s): Noriko Yoneda-Kato
  • Organizer: Cold Spring Harbor Laboratory Meeting
  • Int'l Joint Research