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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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 2

Identification of the Tribbles-binding site in ACC1.

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Identification of the Tribbles-binding site in ACC1. (A) Schematic repre...
(A) Schematic representation of ACC1 deletion mutants. The results of Trib1 binding are summarized on the right. (B) GST-control and GST-Trib1 fusion proteins were incubated with 293T cell lysates containing FLAG-tagged ACC1WT and deletion mutant proteins. Bound proteins were detected by immunoblotting with an antibody against a FLAG epitope. The GST-Trib1–fused protein was visualized by CBB staining to evaluate its amount. (C) Schematic representation of ACC1 deletion mutants minimized for ACC1-Trib1 binding. The results of Trib1 binding are summarized on the right. (D and E) GST-control and GST-Trib1 fusion proteins were incubated with 293T cell lysates containing FLAG-ACC1/200–275 (D). GST-control and all GST-Tribbles (GST-Trib1, GST-Trib2, and GST-Trib3) fusion proteins were incubated with 293T cell lysates containing FLAG-ACC1/Δ200–275 and ACC1/Δ275–324 (E). Bound proteins were detected by immunoblotting with an antibody against a FLAG epitope. GST-Tribbles–fused proteins were visualized by CBB staining to evaluate their amounts.