title: Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation.
abstract: Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation.
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK.
authors.forename: Vinay
authors.initials: V
authors.lastname: Bulusu
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK.
authors.forename: Sergey
authors.initials: S
authors.lastname: Tumanov
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK.
authors.forename: Evdokia
authors.initials: E
authors.lastname: Michalopoulou
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Niels J
authors.initials: NJ
authors.lastname: van den Broek
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: MacKay
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhayade
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Schug
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Johan
authors.initials: J
authors.lastname: Vande Voorde
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK. Electronic address: jurre.kamphorst@glasgow.ac.uk.
authors.forename: Jurre J
authors.initials: JJ
authors.lastname: Kamphorst
mesh_terms: D000106:Acetate-CoA Ligase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000085:Acetates / Q000737:chemistry / Q000378:metabolism*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D002247:Carbon Isotopes / Q000737:chemistry; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media / Q000737:chemistry; D006657:Histones / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D055442:Metabolome; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D044967:Serum / Q000737:chemistry
chemical_list: D000085:Acetates; D002247:Carbon Isotopes; D003470:Culture Media; D006657:Histones; D034741:RNA, Small Interfering; D000105:Acetyl Coenzyme A; D000106:Acetate-CoA Ligase
keywords: acetate; acetyl-CoA synthetase 2; cancer metabolism; enzyme localization; histone acetylation; histone deacetylation; hypoxia; lipogenesis; metabolite compartmentalization; stable isotope tracing