title: The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment.
abstract: Optimal stress signaling by Hypoxia Inducible Factor 2 (HIF-2) during low oxygen states or hypoxia requires coupled actions of a specific coactivator/lysine acetyltransferase, Creb binding protein (CBP), and a specific deacetylase, Sirtuin 1 (SIRT1). We recently reported that acetylation of HIF-2 by CBP also requires a specific acetyl CoA generator, acetate-dependent acetyl CoA synthetase 2 (ACSS2). In this study, we demonstrate that ACSS2/HIF-2 signaling is active not only during hypoxia, but also during glucose deprivation. Acetate levels increase during stress and coincide with maximal HIF-2α acetylation and CBP/HIF-2α complex formation. Exogenous acetate induces HIF-2α acetylation, CBP/HIF-2α complex formation, and HIF-2 signaling. ACSS2 and HIF-2 are required for maximal colony formation, proliferation, migration, and invasion during stress. Acetate also stimulates flank tumor growth and metastasis in mice in an ACSS2 and HIF-2 dependent manner. Thus, ACSS2/CBP/SIRT1/HIF-2 signaling links nutrient sensing and stress signaling with cancer growth and progression in mammals.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Nagati
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Hogg
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Alok
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Department of Medicine, Veterans Affairs North Texas Health Care System, Dallas, Texas, United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Garcia
mesh_terms: D000106:Acetate-CoA Ligase / Q000378:metabolism; D000085:Acetates / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D059016:Tumor Microenvironment; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000106:Acetate-CoA Ligase; D000085:Acetates; D051792:Basic Helix-Loop-Helix Proteins; D050882:CREB-Binding Protein; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D056564:Sirtuin 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C494363:CREBBP protein, human; C447939:SIRT1 protein, human; C000595379:ACSS2 protein, human