title: Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death.
abstract: The promyelocytic leukemia protein (PML) is a tumor suppressor that is expressed at a low level in various cancers. Although post-translational modifications including SUMOylation, phosphorylation, and ubiquitination have been found to regulate the stability or activity of PML, little is known about the role of its acetylation in the control of cell survival. Here we demonstrate that acetylation of lysine 487 (K487) and SUMO1 conjugation of K490 at PML protein are mutually exclusive. We found that hydrogen peroxide (H2O2) promotes PML deacetylation and identified SIRT1 and SIRT5 as PML deacetylases. Both SIRT1 and SIRT5 are required for H2O2-mediated deacetylation of PML and accumulation of nuclear PML protein in HeLa cells. Knockdown of SIRT1 reduces the number of H2O2-induced PML-nuclear bodies (NBs) and increases the survival of HeLa cells. Ectopic expression of wild-type PML but not the K487R mutant rescues H2O2-induced cell death in SIRT1 knockdown cells. Furthermore, ectopic expression of wild-type SIRT5 but not a catalytic defective mutant can also restore H2O2-induced cell death in SIRT1 knockdown cells. Taken together, our findings reveal a novel regulatory mechanism in which SIRT1/SIRT5-mediated PML deacetylation plays a role in the regulation of cancer cell survival.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA.
authors.forename: D
authors.initials: D
authors.lastname: Guan
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Lim
authors.affiliation: H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lam
authors.affiliation: H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Seto
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Kao
mesh_terms: D000107:Acetylation; D020816:Amino Acid Motifs; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D006861:Hydrogen Peroxide; C447939:SIRT1 protein, human; C508544:SIRT5 protein, human; D056564:Sirtuin 1; D037761:Sirtuins