TY - JOUR
T1 - Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-Induced cell death
AU - Guan, D.
AU - Lim, J. H.
AU - Peng, L.
AU - Liu, Y.
AU - Lam, M.
AU - Seto, E.
AU - Kao, H. Y.
N1 - Funding Information:
expression plasmids; and Dr. David Samols for his comments on the manuscript. This project is supported by RO1 HL093269 and DK078965 to H-YK, RO1 CA169210 to ES, and P30 AR-039750 to the Case Western Reserve University Skin Diseases Research Center and the Ohio Department of Development Center for Innovative Immunosuppressive Therapeutics (Prime Award, TECH09-023).
PY - 2014/7
Y1 - 2014/7
N2 - 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 thestability 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 (H 2O2) promotes PML deacetylation and identified SIRT1 and SIRT5 as PML deacetylases. Both SIRT1 and SIRT5 are required for H 2O2-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.
AB - 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 thestability 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 (H 2O2) promotes PML deacetylation and identified SIRT1 and SIRT5 as PML deacetylases. Both SIRT1 and SIRT5 are required for H 2O2-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.
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U2 - 10.1038/cddis.2014.185
DO - 10.1038/cddis.2014.185
M3 - Article
C2 - 25032863
AN - SCOPUS:84905442969
SN - 2041-4889
VL - 5
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 7
M1 - e1340
ER -