Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development
Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, Noriko Yoneda-Kato
Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, Noriko Yoneda-Kato
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Research Article Oncology

Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development

Abstract

Cancer cells reprogram lipid metabolism during their malignant progression, but limited information is currently available on the involvement of alterations in fatty acid synthesis in cancer development. We herein demonstrate that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for fatty acid synthesis, plays a critical role in regulating the growth and differentiation of leukemia-initiating cells. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPA, a transcription factor regulating myeloid differentiation, for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). We identified ACC1 as a target of the Trib1-COP1 complex and found that an ACC1 mutant resistant to degradation because of the lack of a Trib1-binding site attenuated complex-driven leukemogenesis. Stable ACC1 protein expression suppressed the growth-promoting activity and increased ROS levels with the consumption of NADPH in a primary bone marrow culture, and delayed the onset of AML with increases in mature myeloid cells in mouse models. ACC1 promoted the terminal differentiation of Trib1-COP1–expressing cells and eradicated leukemia-initiating cells in the early phase of leukemic progression. These results indicate that ACC1 is a natural inhibitor of AML development. The upregulated expression of the ACC1 protein has potential as an effective strategy for cancer therapy.

Authors

Hidenori Ito, Ikuko Nakamae, Jun-ya Kato, Noriko Yoneda-Kato

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Figure 6

ACC1 stabilization induces the loss of self-renewal activity in leukemia-initiating cells.

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ACC1 stabilization induces the loss of self-renewal activity in leukemia...
(A and B) GFP-positive BM cells expressing Trib1/COP1 together with and without Helix1mut were sorted and plated in methylcellulose-based medium. Colony numbers were counted after 10 days and replated in fresh medium for serial colony assays (A, left panel). Plates from the first culture and the fourth serial culture are shown (A, right panel). May-Grünwald-Giemsa stain (original magnification, ×400) and frequency of neutrophils (n = 3) in colony-forming cells from the first culture (B). (C–H) BM cells from the early phase of Trib1-COP1 control mice and mice with Helix1mut-cotransduced BM (10 weeks after BM transplantation) were analyzed. (C) FACS analysis for immature (Mac-1+Gr-1lo) and differentiated (Mac-1hiGr-1hi) granulocytes. The population of GFP-positive cells in BM is shown in the top panels. (D) GFP-positive cells were sorted and plated for colony assays. (E) Kaplan-Meier survival curves of secondary transplanted mice. Sublethally irradiated mice received 1 × 105 GFP-positive BM cells each from two Trib1/COP1 and two Helix1mut mice. (F) A detailed FACS analysis of GFP-positive BM cells from secondary transplanted mice in E. Lin*–Sca-1– cells were separated into 3 fractions: c-KithiMac-1– (fraction A), c-Kit+Mac-1+ (fraction B), and c-Kitlo/–Mac-1+ (fraction C). (G and H) GFP-positive BM cells from the early phase of Trib1/COP1 (n = 4) and Helix1mut (n = 4) mice were analyzed to measure acetyl-CoA levels (G), ROS levels, the NADP+/NADPH ratio, and the GSH/GSSG ratio (H). (I) Proposed model of the ACC1-mediated pathway and effects on leukemia cells. P values were calculated by Student’s t test (*P < 0.05, **P < 0.01, ***P < 0.001) in A, B, D, G, and H and by log-rank test in E. Data are the average of 2 independent experiments with 4 dishes (A and D) and 4 independent experiments (G and H) shown as mean ± SEM.