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 3

Construction of ACC1 point mutants resistant to Trib1-COP1–mediated degradation.

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Construction of ACC1 point mutants resistant to Trib1-COP1–mediated degr...
(A) Sequence alignment of residues 200–275 of human ACC1 with compatible residues of various species. The region includes two α-helices (Helix1: residues 216–225; Helix2: residues 233–253) marked in orange and other conserved residues shown in gray. (B) Structure of the biotin carboxylase (BC) domain of ACC1. Helix1 and Helix2 (in orange) are positioned at the outside of the ATP-binding site (in blue). Mutants of Helix1 and Helix2 were constructed by replacement of 3 residues positioned at the interaction surfaces with alanine (Helix1mut: P216A, K217A, and E220A; Helix2mut: P233A, Q235A, and W238A; shown in red). This model is generated by the human ACC1 full crystal structure (PDB:6G2D) with PyMOL (http://www.pymol.org). (C) Schematic representation of ACC1 point mutants for the ACC1-Trib1 binding and ubiquitination sites. The results of Trib1 binding and degradation are summarized on the right. NT, not tested. (D) GST-control and all GST-Tribbles (GST-Trib1, GST-Trib2, and GST-Trib3) fusion proteins were incubated with 293T cell lysates containing FLAG-ACC1WT, Helix1mut, and Helix2mut. 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. (E and F) Helix1mut and K1759R are resistant to degradation. 293T cells were transfected with the combination of vectors shown at the top. Cell lysates were analyzed by immunoblotting with antibodies against a FLAG epitope, COP1, an HA epitope, and γ-tubulin (E). Relative amounts of proteins were quantified using ImageJ software (NIH) (F).