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 7

ACC1 is downregulated in human AML and stabilized ACC1 partially suppresses MLL-AF9–induced AML.

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ACC1 is downregulated in human AML and stabilized ACC1 partially suppres...
(A) Microarray data analysis of the ACC1 expression in human AML. Gene expression data of normal BMs from healthy donors (n = 9) and AML patient samples (n = 285) were obtained from the GEO data sets. (B) ACC1 protein and mRNA levels in human leukemic cell lines. Cell lysates from normal BM, a CML cell line (K562), and AML cell lines (HL60, OCI-AML3, THP-1, KY821, and U937) were analyzed by immunoblotting with antibodies against ACC1, COP1, and γ-tubulin. Total RNA was analyzed by semi-qRT-PCR using a pair of primers specific to ACC1, Trib1, and GAPDH. (C–F) Primary BM cells were infected with retroviruses expressing MLL-AF9, BCR-ABL, and Trib1- and COP1-IRES-GFP together with and without ACC1 Helix1mut. Sorted GFP-positive cells were cultured in BM medium. Cell numbers were counted for growth curves (C). Total RNA extracted from GFP-positive cells in C was analyzed by semi-qRT-PCR using a pair of primers specific to MLL-AF9, BCR-ABL (D), human and mouse (h&m) ACC1 (E), and β-actin (D and E). Cell lysates of GFP-positive cells in C were analyzed by immunoblotting with antibodies against ACC1 and γ-tubulin (E). Relative amounts of mRNAs (h&mACC1/β-actin) were quantified using ImageJ software (E, bottom panels). GFP-positive cells in C were transferred to IL-3–containing medium with low glucose (1 g/L) and analyzed to measure ROS levels, the NADP+/NADPH ratio, and the GSH/GSSG ratio (F). Data are the average of 3 independent experiments (C and F) shown as mean ± SEM. (G) Survival curves of transplanted mice with BM expressing MLL-AF9-IRES-GFP and BCR-ABL-IRES-GFP together with and without ACC1 Helix1mut. Results are derived from 3 independent transfer experiments. P values were calculated with Student’s t test (*P < 0.05, **P < 0.01, ***P < 0.001) in A, C, and F and with log-rank test in G.