title: Acetate dependence of tumors.
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.
authors.affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Comerford
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xinlin
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Agnes K
authors.initials: AK
authors.lastname: Witkiewicz
authors.affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Walters
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Mohammed N
authors.initials: MN
authors.lastname: Tantawy
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Allie
authors.initials: A
authors.lastname: Fu
authors.affiliation: Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
authors.affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: steven.mcknight@utsouthwestern.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: McKnight
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: benjamin.tu@utsouthwestern.edu.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Tu
mesh_terms: D000106:Acetate-CoA Ligase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000085:Acetates / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000473:pathology
chemical_list: D000085:Acetates; D000105:Acetyl Coenzyme A; C000595379:ACSS2 protein, human; C000595378:ACSS2 protein, mouse; D000106:Acetate-CoA Ligase