title: Class I histone deacetylases localize to the endoplasmic reticulum and modulate the unfolded protein response.
abstract: Post-translational modification through protein acetylation is emerging as an important mode of cellular regulation. We have previously demonstrated the role that glucose-regulated protein 78 kDa (GRP78) acetylation and subsequent activation of the unfolded protein response (UPR) play in the antitumor activity of class I histone deacetylase (HDAC) inhibitors, which primarily target class I HDACs. In this study, we explored the contributory role these class I HDACs may play in UPR regulation. Binding studies were performed using immunoprecipitation/immunoblotting following dual-transfection with HA-tagged GRP78 and FLAG-tagged HDACs. Subcellular localization was performed using Western blot of fractionated cell lysates and confocal microscopy. Individual HDACs were inhibited using RNA interference. We identified the potential of HDACs 1, 2, and 3 to bind to GRP78. These HDACs colocalized with GRP78 in the endoplasmic reticulum (ER). Inhibition of individual HDACs resulted in GRP78 acetylation and selective activation of the UPR. Although traditionally viewed as nuclear enzymes, we demonstrate that Class I HDACs localize to the ER, bind to GRP78, and selectively activate the UPR, representing a novel mode of UPR regulation and mechanism of action of HDAC inhibitors.
authors.affiliation: Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Soumen
authors.initials: S
authors.lastname: Kahali
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Sarcar
authors.forename: Antony
authors.initials: A
authors.lastname: Prabhu
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.forename: Prakash
authors.initials: P
authors.lastname: Chinnaiyan
mesh_terms: D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D034622:RNA Interference; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases