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 1

Trib1 recruits COP1 to ACC1, and specifically induces proteasome-mediated degradation.

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Trib1 recruits COP1 to ACC1, and specifically induces proteasome-mediate...
(A) Specific interactions between ACC1 and Tribble proteins in vitro. GST-control, GST-Trib1, GST-Trib2, and GST-Trib3 fusion proteins shown at the top were incubated with 293T cell lysates containing FLAG-tagged ACC1 proteins. Bound proteins were detected by immunoblotting with an antibody against a FLAG epitope. GST-fused proteins were visualized by Coomassie brilliant blue (CBB) staining to evaluate their amounts. (B) The ACC1 protein is downregulated by Trib1-COP1 and Trib2-COP1 as well as Trib3-COP1. 293T cells were transfected with vectors encoding FLAG-ACC1 and GFP-COP1 together with HA-tagged Tribbles (HA-Trib1, HA-Trib2, or HA-Trib3). Cell lysates were analyzed by immunoblotting with antibodies against a FLAG epitope, COP1, an HA epitope, and γ-tubulin. (C) A treatment with MG132 inhibits ACC1 degradation. 293T cells transfected with a combination of vectors encoding FLAG-ACC1, GFP-COP1, and HA-Trib1 were incubated in the presence and absence of MG132 and analyzed by immunoblotting with antibodies against ACC1, COP1, an HA epitope, and γ-tubulin. (D) All Tribbles-COP1 promote the ubiquitination of ACC1. 293T cells were transfected with a combination of vectors shown at the top. Cell lysates were analyzed by immunoprecipitation with an antibody against a FLAG epitope followed by immunoblotting with an antibody against a FLAG epitope, and by immunoblotting with an antibody against COP1. Total RNA was analyzed by semiquantitative RT-PCR (semi-qRT-PCR) using a pair of primers specific to Trib1, Trib2, Trib3, and human GAPDH. (E) ACC1 is degraded through the interaction with Trib1. 293T cells were transfected with a combination of vectors shown at the top. Cell lysates were analyzed by immunoblotting with antibodies against a FLAG epitope, COP1, an HA epitope, MLF1, and γ-tubulin.