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Mol Cell. 2016 Dec 1;64(5):859-874. doi: 10.1016/j.molcel.2016.10.014. Epub 2016 Nov 17.

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth.

Author information

1
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.
2
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
3
Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Fudan University, Shanghai 201203, China.
5
Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA.
6
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
7
Children's Research Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA.
8
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.
9
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.
10
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
11
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.

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.

KEYWORDS:

Warburg effect; acetyl-CoA acetyltransferase 1; arecoline hydrobromide; cancer metabolism; cancer therapy; mitochondria; pyruvate dehydrogenase complex; tetramer formation; tyrosine phosphorylation

Comment in

PMID:
27867011
PMCID:
PMC5135630
DOI:
10.1016/j.molcel.2016.10.014
[Indexed for MEDLINE]
Free PMC Article

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