Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth

Jun Fan, Ruiting Lin, Siyuan Xia, Dong Chen, Shannon E. Elf, Shuangping Liu, Yaozhu Pan, Haidong Xu, Zhiyu Qian, Mei Wang, Changliang Shan, Lu Zhou, Qun Ying Lei, Yuancheng Li, Hui Mao, Benjamin H. Lee, Jessica Sudderth, Ralph J. DeBerardinis, Guojing Zhang, Taofeek OwonikokoManila Gaddh, Martha L. Arellano, Hanna J. Khoury, Fadlo R. Khuri, Sumin Kang, Paul W. Doetsch, Sagar Lonial, Titus J. Boggon, Walter J. Curran, Jing Chen

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)859-874
Number of pages16
JournalMolecular cell
Volume64
Issue number5
DOIs
StatePublished - Dec 1 2016

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Fan, J., Lin, R., Xia, S., Chen, D., Elf, S. E., Liu, S., Pan, Y., Xu, H., Qian, Z., Wang, M., Shan, C., Zhou, L., Lei, Q. Y., Li, Y., Mao, H., Lee, B. H., Sudderth, J., DeBerardinis, R. J., Zhang, G., ... Chen, J. (2016). Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth. Molecular cell, 64(5), 859-874. https://doi.org/10.1016/j.molcel.2016.10.014