title: Lysine demethylase KDM4A associates with translation machinery and regulates protein synthesis.
abstract: Chromatin-modifying enzymes are predominantly nuclear; however, these factors are also localized to the cytoplasm, and very little is known about their role in this compartment. In this report, we reveal a non-chromatin-linked role for the lysine-specific demethylase KDM4A. We demonstrate that KDM4A interacts with the translation initiation complex and affects the distribution of translation initiation factors within polysome fractions. Furthermore, KDM4A depletion reduced protein synthesis and enhanced the protein synthesis suppression observed with mTOR inhibitors, which paralleled an increased sensitivity to these drugs. Finally, we demonstrate that JIB-04, a JmjC demethylase inhibitor, suppresses translation initiation and enhances mTOR inhibitor sensitivity. These data highlight an unexpected cytoplasmic role for KDM4A in regulating protein synthesis and suggest novel potential therapeutic applications for this class of enzyme.
  
  
  CONCLUSIONS
  This report documents an unexpected cytoplasmic role for the lysine demethylase KDM4A. We demonstrate that KDM4A interacts with the translation initiation machinery, regulates protein synthesis and, upon coinhibition with mTOR inhibitors, enhances the translation suppression and cell sensitivity to these therapeutics.
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Capucine
authors.initials: C
authors.lastname: Van Rechem
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Black
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Myriam
authors.initials: M
authors.lastname: Boukhali
authors.affiliation: Massachusetts General Hospital Department of Pathology and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Aryee
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gräslund
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts. jwhetstine@hms.harvard.edu.
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Whetstine
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D010442:Peptide Chain Initiation, Translational; D010448:Peptide Initiation Factors / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012269:Ribosomal Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000631:Aminopyridines; D006835:Hydrazones; C585278:JIB-04; D010448:Peptide Initiation Factors; D047428:Protein Kinase Inhibitors; D012269:Ribosomal Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D058570:TOR Serine-Threonine Kinases; D008239:Lysine