Acetate dependence of tumors

Sarah A Comerford, Zhiguang Huang, Xinlin Du, Yun Wang, Ling Cai, Agnieszka Witkiewicz, Holly Walters, Mohammed N. Tantawy, Allie Fu, H. Charles Manning, Jay D Horton, Robert E Hammer, Steven L McKnight, Benjamin P Tu

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248 Scopus citations

Abstract

Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.

Original languageEnglish (US)
Pages (from-to)1591-1602
Number of pages12
JournalCell
Volume159
Issue number7
DOIs
StatePublished - Dec 18 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Comerford, S. A., Huang, Z., Du, X., Wang, Y., Cai, L., Witkiewicz, A., Walters, H., Tantawy, M. N., Fu, A., Manning, H. C., Horton, J. D., Hammer, R. E., McKnight, S. L., & Tu, B. P. (2014). Acetate dependence of tumors. Cell, 159(7), 1591-1602. https://doi.org/10.1016/j.cell.2014.11.020