title: Induction of MHC class I molecule cell surface expression and epigenetic activation of antigen-processing machinery components in a murine model for human papilloma virus 16-associated tumours.
abstract: Epigenetic events play an important role in tumour progression and also contribute to escape of the tumour from immune surveillance. In this study, we investigated the up-regulation of major histocompatibility complex (MHC) class I surface expression on tumour cells by epigenetic mechanisms using a murine tumour cell line expressing human E6 and E7 human papilloma virus 16 (HPV16) oncogenes and deficient in MHC class I expression, as a result of impaired antigen-presenting machinery (APM). Treatment of the cells with the histone deacetylase inhibitor Trichostatin A, either alone or in combination with the DNA demethylating agent 5-azacytidine, induced surface re-expression of MHC class I molecules. Consequently, the treated cells became susceptible to lysis by specific cytotoxic T lymphocytes. Further analysis revealed that epigenetic induction of MHC class I surface expression was associated with the up-regulation of APM genes [transporter associated with antigen processing 1 (TAP-1), TAP-2, low-molecular-mass protein 2 (LMP-2) and LMP-7]. The results demonstrate that expression of the genes involved in APM are modulated by epigenetic mechanisms and suggest that agents modifying DNA methylation and/or histone acetylation have the potential to change the effectiveness of antitumour immune responses and therapeutically may have an impact on immunological output.
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Jasper
authors.initials: J
authors.lastname: Manning
authors.forename: Marie
authors.initials: M
authors.lastname: Indrova
authors.forename: Barbora
authors.initials: B
authors.lastname: Lubyova
authors.forename: Hana
authors.initials: H
authors.lastname: Pribylova
authors.forename: Jana
authors.initials: J
authors.lastname: Bieblova
authors.forename: Jiri
authors.initials: J
authors.lastname: Hejnar
authors.forename: Jana
authors.initials: J
authors.lastname: Simova
authors.forename: Tana
authors.initials: T
authors.lastname: Jandlova
authors.forename: Jan
authors.initials: J
authors.lastname: Bubenik
authors.forename: Milan
authors.initials: M
authors.lastname: Reinis
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000276:immunology*; D005805:Genes, MHC Class I; D006657:Histones / Q000378:metabolism; D052162:Human papillomavirus 16; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000821:virology; D030361:Papillomavirus Infections / Q000150:complications*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D001374:Azacitidine