title: Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism.
abstract: Lysine residues are subject to a multitude of reversible post-translational modifications, including acetylation and SUMOylation. In the heart, enhancement of lysine acetylation or SUMOylation using histone deacetylase (HDAC) inhibitors or SUMO-1 gene transfer, respectively, has been shown to be cardioprotective. Here, we addressed whether there is crosstalk between lysine acetylation and SUMOylation in the heart. Treatment of cardiomyocytes and cardiac fibroblasts with pharmacological inhibitors of HDAC catalytic activity robustly increased conjugation of SUMO-1, but not SUMO-2/3, to several high molecular weight proteins in both cell types. The use of a battery of selective HDAC inhibitors and short hairpin RNAs demonstrated that HDAC2, which is a class I HDAC, is the primary HDAC isoform that controls cardiac protein SUMOylation. HDAC inhibitors stimulated protein SUMOylation in the absence of de novo gene transcription or protein synthesis, revealing a post-translational mechanism of HDAC inhibitor action. HDAC inhibition did not suppress the activity of de-SUMOylating enzymes, suggesting that increased protein SUMOylation in HDAC inhibitor-treated cells is due to stimulation of SUMO-1 conjugation rather than blockade of SUMO-1 cleavage. Consistent with this, multiple components of the SUMO conjugation machinery were capable of being acetylated in vitro. These findings reveal a novel role for reversible lysine acetylation in the control of SUMOylation in the heart, and suggest that cardioprotective actions of HDAC inhibitors are in part due to stimulation of protein SUMO-1-ylation in myocytes and fibroblasts.
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Weston W
authors.initials: WW
authors.lastname: Blakeslee
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Wysoczynski
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Kristofer S
authors.initials: KS
authors.lastname: Fritz
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Nyborg
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Mair E A
authors.initials: ME
authors.lastname: Churchill
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. Electronic address: timothy.mckinsey@ucdenver.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D055162:Biocatalysis / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation / Q000187:drug effects*
chemical_list: D056572:Histone Deacetylase Inhibitors; D025842:SUMO-1 Protein; D010450:Endopeptidases; D006655:Histone Deacetylases; D008239:Lysine
keywords: Acetylation; HDAC; SUMO