title: Histone acetylation regulates intracellular pH.
abstract: Differences in global levels of histone acetylation occur in normal and cancer cells, although the reason why cells regulate these levels has been unclear. Here we demonstrate a role for histone acetylation in regulating intracellular pH (pH(i)). As pH(i) decreases, histones are globally deacetylated by histone deacetylases (HDACs), and the released acetate anions are coexported with protons out of the cell by monocarboxylate transporters (MCTs), preventing further reductions in pH(i). Conversely, global histone acetylation increases as pH(i) rises, such as when resting cells are induced to proliferate. Inhibition of HDACs or MCTs decreases acetate export and lowers pH(i), particularly compromising pH(i) maintenance in acidic environments. Global deacetylation at low pH is reflected at a genomic level by decreased abundance and extensive redistribution of acetylation throughout the genome. Thus, acetylation of chromatin functions as a rheostat to regulate pH(i) with important implications for mechanism of action and therapeutic use of HDAC inhibitors.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: McBrian
authors.forename: Iman Saramipoor
authors.initials: IS
authors.lastname: Behbahan
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrari
authors.forename: Trent
authors.initials: T
authors.lastname: Su
authors.forename: Ta-Wei
authors.initials: TW
authors.lastname: Huang
authors.forename: Kunwu
authors.initials: K
authors.lastname: Li
authors.forename: Candice S
authors.initials: CS
authors.lastname: Hong
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.forename: Maria
authors.initials: M
authors.lastname: Vogelauer
authors.forename: David B
authors.initials: DB
authors.lastname: Seligson
authors.forename: Siavash K
authors.initials: SK
authors.lastname: Kurdistani
mesh_terms: D000085:Acetates; D000107:Acetylation; D050260:Carbohydrate Metabolism; D002843:Chromatin; D005786:Gene Expression Regulation; D005947:Glucose / Q000502:physiology; D005973:Glutamine / Q000502:physiology; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006877:Hydroxamic Acids / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D019289:Pyruvic Acid / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D000085:Acetates; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D027501:Monocarboxylic Acid Transporters; D005973:Glutamine; D009536:Niacinamide; C012589:trichostatin A; D019289:Pyruvic Acid; D006655:Histone Deacetylases; D005947:Glucose