title: Regulation of HLA-DR peptide occupancy by histone deacetylase inhibitors.
abstract: Numerous molecular effects have been attributed to histone deacetylase inhibitors (HDACI's), including the induction of major histocompatibility (MHC) genes. Here we report that one FDA approved HDACI, Vorinostat, and a second HDACI currently in clinical trials, Entinostat, reduce the ratio of class II associated invariant peptide (CLIP) to the MHC class II molecule, HLA-DR, indicating an increase in the non-CLIP peptides bound to HLA-DR. The HDACI effects are apparent with immortalized B-cells, HLA-DR constitutive melanoma cells and with melanoma cells expressing HLA-DR due to transformation with an expression vector for the HLA-DR gene co-activator, CIITA. Entinostat treatment leads to upregulation of Cathepsin L1, and the HLA-DR peptidome of the Entinostat treated cells is consistent with increased Cathepsin L1 mediated proteolysis. These results indicate that HDACI treatments may alter the HLA-DR peptidome of cells in patients and provide a way to identify novel immunogens for vaccinations and the study of autoantigens.
authors: Department of Molecular Medicine; Morsani College of Medicine; University of South Florida; Tampa, FL USA.
authors: Kevin
authors: K
authors: Cronin
authors: Hernando
authors: H
authors: Escobar
authors: Karoly
authors: K
authors: Szekeres
authors: Eduardo
authors: E
authors: Reyes-Vargas
authors: Alan L
authors: AL
authors: Rockwood
authors: Mark C
authors: MC
authors: Lloyd
authors: Julio C
authors: JC
authors: Delgado
authors: George
authors: G
authors: Blanck
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D001402:B-Lymphocytes / Q000737:chemistry / Q000187:drug effects; D001549:Benzamides / Q000378:metabolism*; D056668:Cathepsin L / Q000378:metabolism; D002460:Cell Line; D006684:HLA-DR Antigens / Q000032:analysis*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism*; D059748:Proteolysis; D011725:Pyridines / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D001549:Benzamides; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; C045084:invariant chain; C118739:entinostat; D000077337:Vorinostat; D056668:Cathepsin L
keywords: HLA-DR peptide occupancy; antigenic peptide; cathepsin; histone deacetylase inhibitors; major histocompatibility class II