title: Using Histone Deacetylase Inhibitors to Analyze the Relevance of HDACs for Translation.
abstract: Gene expression is regulated in part through the reversible acetylation of histones, by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). HAT activity results in the addition of acetyl groups on the lysine residues of histone tails leading to decondensation of the chromatin, and increased gene transcription in general, whereas HDACs remove these acetyl groups, thus leading to an overall suppression of gene transcription. Recent evidence has elucidated that histones are not the only components of the proteome that are targeted by HATs and HDACs. A large number of nonhistone proteins undergo posttranslational acetylation. They include proteins involved in mRNA stability, protein localization and degradation, as well as protein-protein and protein-DNA interactions. In recent years, numerous studies have discovered increased HDAC expression and/or activity in numerous disease states, including cancer, where the upregulation of HDAC family members leads to dysregulation of genes and proteins involved in cell proliferation, cell cycle regulation, and apoptosis. These observations have pushed HDAC inhibitors (HDACi) to the forefront of therapeutic development of oncological conditions. HDACi, such as Vorinostat (Suberoylanilide hydroxamic acid (SAHA)), affect cancer cells in part by suppressing the translation of key proteins linked to tumorigenesis, such as cyclin D1 and hypoxia inducible factor 1 alpha (HIF-1α). Herein we describe methodologies to analyze the impact of the HDACi Vorinostat on HIF-1α translational regulation and downstream effectors.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Hutt
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
authors.forename: Daniela Martino
authors.initials: DM
authors.lastname: Roth
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, Bordeaux, 33077, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Marchal
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, Bordeaux, 33077, France. marionb@ibgc.cnrs.fr.
authors.forename: Marion
authors.initials: M
authors.lastname: Bouchecareilh
mesh_terms: D000107:Acetylation; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D039621:Eukaryotic Initiation Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat
chemical_list: C530104:CCND1 protein, human; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D039621:Eukaryotic Initiation Factor-3; C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007976:Leupeptins; D034741:RNA, Small Interfering; C000613347:dimethyloxallyl glycine; D019938:Cyclin D1; D000077337:Vorinostat; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D003676:Deferoxamine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D005998:Glycine
keywords: HDAC; HDACi; HIF-1α; Translation; Vorinostat