title: The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition.
abstract: Hypoxia inducible factor 1α (HIF-1α) is a master regulator of tumor angiogenesis being one of the major targets for cancer therapy. Previous studies have shown that Histone Deacetylase Inhibitors (HDACi) block tumor angiogenesis through the inhibition of HIF-1α expression. As such, Vorinostat (Suberoylanilide Hydroxamic Acid/SAHA) and Romidepsin, two HDACis, were recently approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma. Although HDACis have been shown to affect HIF-1α expression by modulating its interactions with the Hsp70/Hsp90 chaperone axis or its acetylation status, the molecular mechanisms by which HDACis inhibit HIF-1α expression need to be further characterized. Here, we report that the FDA-approved HDACi Vorinostat/SAHA inhibits HIF-1α expression in liver cancer-derived cell lines, by a new mechanism independent of p53, prolyl-hydroxylases, autophagy and proteasome degradation. We found that SAHA or silencing of HDAC9 mechanism of action is due to inhibition of HIF-1α translation, which in turn, is mediated by the eukaryotic translation initiation factor--eIF3G. We also highlighted that HIF-1α translation is dramatically inhibited when SAHA is combined with eIF3H silencing. Taken together, we show that HDAC activity regulates HIF-1α translation, with HDACis such as SAHA representing a potential novel approach for the treatment of hepatocellular carcinoma.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Hutt
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.
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, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Vignaud
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, Bordeaux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cullin
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, Bordeaux, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Bouchecareilh
mesh_terms: D045744:Cell Line, Tumor; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D000077337:Vorinostat
chemical_list: D039621:Eukaryotic Initiation Factor-3; C497442:HIF1A protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012097:Repressor Proteins; D000077337:Vorinostat; C486544:HDAC9 protein, human; D006655:Histone Deacetylases