title: Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth.
abstract: Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) regulates pyruvate dehydrogenase complex (PDC) by acetylating pyruvate dehydrogenase (PDH) and PDH phosphatase. How ACAT1 is "hijacked" to contribute to the Warburg effect in human cancer remains unclear. We found that active, tetrameric ACAT1 is commonly upregulated in cells stimulated by EGF and in diverse human cancer cells, where ACAT1 tetramers, but not monomers, are phosphorylated and stabilized by enhanced Y407 phosphorylation. Moreover, we identified arecoline hydrobromide (AH) as a covalent ACAT1 inhibitor that binds to and disrupts only ACAT1 tetramers. The resultant AH-bound ACAT1 monomers cannot reform tetramers. Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity, leading to increased PDC flux and oxidative phosphorylation with attenuated cancer cell proliferation and tumor growth. These findings provide a mechanistic understanding of how oncogenic events signal through distinct acetyltransferases to regulate cancer metabolism and suggest ACAT1 as an anti-cancer target.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: jfan3@emory.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Ruiting
authors.initials: R
authors.lastname: Lin
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Xia
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Elf
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Shuangping
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authors.lastname: Liu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Yaozhu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Changliang
authors.initials: C
authors.lastname: Shan
authors.affiliation: Fudan University, Shanghai 201203, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Fudan University, Shanghai 201203, China.
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Yuancheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Benjamin H
authors.initials: BH
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authors.affiliation: Children's Research Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jessica
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authors.lastname: Sudderth
authors.affiliation: Children's Research Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Guojing
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Taofeek
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authors.lastname: Owonikoko
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Manila
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authors.lastname: Gaddh
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Arellano
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Khoury
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sumin
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authors.lastname: Kang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Doetsch
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: jchen@emory.edu.
authors.forename: Jing
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authors.lastname: Chen
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D011768:Pyruvate Dehydrogenase Complex; D004815:Epidermal Growth Factor; C085706:FLAG peptide; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; C496348:FGFR1 protein, human; D011505:Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Warburg effect; acetyl-CoA acetyltransferase 1; arecoline hydrobromide; cancer metabolism; cancer therapy; mitochondria; pyruvate dehydrogenase complex; tetramer formation; tyrosine phosphorylation