Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors.
Epigenetic mechanisms are involved in regulating chromatin structure and gene expression through repression. In this study, we show that histone deacetylase inhibitors (DAIs) that alter the acetylation of histones in chromatin enhance the expression of several genes on tumor cells including: MHC class I, II, and the costimulatory molecule CD40. Enhanced transcription results in a significant increase in protein expression on the tumor cell surface, and expression can be elicited on some tumors that are unresponsive to IFN-gamma. The magnitude of induction of these genes cannot be explained by the effect of DAIs on the cell cycle or enhanced apoptosis. Induction of class II genes by DAIs was accompanied by activation of a repressed class II transactivator gene in a plasma cell tumor but, in several other tumor cell lines, class II was induced in the apparent absence of class II transactivator transcripts. These findings also suggest that the abnormalities observed in some tumors in the expression of genes critical to tumor immunity may result from epigenetic alterations in chromatin and gene regulation in addition to well-established mutational mechanisms.
Magner
W J
WJ
Departments of. Immunology, Biophysics, and Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Kazim
A L
AL
Stewart
C
C
Romano
M A
MA
Catalano
G
G
Grande
C
C
Keiser
N
N
Santaniello
F
F
Tomasi
T B
TB
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis* / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002843:Chromatin / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D005805:Genes, MHC Class I / Q000187:drug effects*; D005802:Genes, MHC Class II / Q000187:drug effects*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D002843:Chromatin; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; C012589:trichostatin A; D007371:Interferon-gamma