Publication

Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

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Last modified
  • 03/05/2025
Type of Material
Authors
    Jun Fan, Emory UniversityRuiling Lin, Emory UniversitySiyuan Xia, Emory UniversityDong Chen, Emory UniversityShannon E. Elf, Emory UniversityShuangping Liu, Emory UniversityYaozhu Pan, Emory UniversityHaidong Xu, Emory UniversityZhiyu Qian, Emory UniversityMei Wang, Emory UniversityChangliang Shan, Emory UniversityLu Zhou, Fudan UniversityQun-Ying Lei, Fudan UniversityYuancheng Li, Emory UniversityHui Mao, Emory UniversityBenjamin H. Lee, Novartis Institutes for BioMedical ResearchJessica Sudderth, UT Southwestern Medical CenterRalph J. DeBerardinis, UT Southwestern Medical CenterGuojing Zhang, Emory UniversityTaofeek Owonikoko, Emory UniversityManila Gaddh, Emory UniversityMartha Arellano, Emory UniversityHanna Khoury, Emory UniversityFadlo Khuri, Emory UniversitySu Kang, Emory UniversityPaul Doetsch, Emory UniversitySagar Lonial, Emory UniversityTitus J. Boggon, Yale UniversityWalter Curran, Emory UniversityJing Chen, Emory University
Language
  • English
Date
  • 2016-12-01
Publisher
  • Elsevier (Cell Press)
Publication Version
Copyright Statement
  • © 2016 Elsevier Inc.
Final Published Version (URL)
Title of Journal or Parent Work
ISSN
  • 1097-2765
Volume
  • 64
Issue
  • 5
Start Page
  • 859
End Page
  • 874
Grant/Funding Information
  • This work was supported in part by NIH grants CA140515, CA183594, CA174786 (J.C.), CA175316 (S.K.), CA169937 (H.M.), T.J. Martell Foundation (J.C.), Winship Cancer Institute #IRG-14-188-01 seed grant from the American Cancer Society (J.F.), Winship Invest$, Emory University (J.F.), and Hematology Tissue Bank of Emory University School of Medicine (H.J.K.).
Supplemental Material (URL)
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.
Author Notes
  • Correspondence to: jfan3@emory.edu (J.F.), or jchen@emory.edu (J.C.). Jun Fan, Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. Phone: 404-778-5826; Fax: 404-778-5530; Jing Chen, Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. Phone: 404-778-5274; Fax: 404-778-5530.
Keywords
Research Categories
  • Health Sciences, Oncology
  • Health Sciences, Radiology

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