Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development
Hidenori Ito, … , Jun-ya Kato, Noriko Yoneda-Kato
Hidenori Ito, … , Jun-ya Kato, Noriko Yoneda-Kato
Published June 15, 2021
Citation Information: J Clin Invest. 2021;131(12):e141529. https://doi.org/10.1172/JCI141529.
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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 4

Stabilized ACC1 suppresses cell growth and increases ROS levels and NADPH consumption.

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Stabilized ACC1 suppresses cell growth and increases ROS levels and NADP...
(A and B) Primary BM cells were infected with retroviruses expressing Trib1- and COP1-IRES-GFP in the presence and absence of ACC1-specific siRNA (siACC1). GFP-positive cells were sorted by flow cytometry and cultured in BM medium. Cell numbers were counted for growth curves (A). GFP-positive cells in A were transferred to IL-3–containing medium with low glucose (1 g/L), maintained for 3 days, and analyzed to measure ROS levels (B). P values were calculated with Student’s t test (*P < 0.05, **P < 0.01). Data are the average of 3 independent experiments (A and B) shown as mean ± SEM. (C–F) Primary BM cells were infected with retroviruses expressing Trib1- and COP1-IRES-GFP together with and without ACC1WT, K1759R, and Helix1mut. GFP-positive cells were sorted by flow cytometry and cultured in BM medium. Cell numbers were counted for growth curves (C). Cell lysates of GFP-positive cells in C were analyzed by immunoblotting with antibodies against ACC1 and γ-tubulin (D, left). Total RNA was analyzed by semi-qRT-PCR using a pair of primers specific to human ACC1 (hACC1) Trib1, COP1, and β-actin (D, right). Relative amounts of proteins (hACC1/γ-tubulin) and mRNAs (hACC1/β-actin) were quantified using ImageJ software (D, bottom panels). GFP-positive cells in C were transferred to IL-3–containing medium with low glucose (1 g/L), maintained in the absence and presence of 1 mM N-acetylcysteine (NAC) for 3 days, and analyzed to measure ROS levels (E) and the NADP+/NADPH ratio (F). P values were calculated with 1-way ANOVA with Tukey’s multiple-comparison post-test (*P < 0.05, **P < 0.01, ***P < 0.001). Data are the average of 3 independent experiments (C, E, and F) shown as mean ± SEM.