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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2006

Open Access 01-06-2006 | Research

Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid

Authors: María de Lourdes Mora-García, Alfonso Duenas-González, Jorge Hernández-Montes, Erick De la Cruz-Hernández, Enrique Pérez-Cárdenas, Benny Weiss-Steider, Edelmiro Santiago-Osorio, Vianney Francisco Ortíz-Navarrete, Víctor Hugo Rosales, David Cantú, Marcela Lizano-Soberón, Martha Patricia Rojo-Aguilar, Alberto Monroy-García

Published in: Journal of Translational Medicine | Issue 1/2006

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Abstract

Background

DNA hypermethylation and histone deacetylation are epigenetic events that contribute to the absence or downregulated expression of different components of the tumor recognition complex. These events affect the processing and presentation of antigenic peptides to CTLs by HLA class-I molecules. In this work evaluated the effect of the DNA hypomethylating agent hydralazine and the histone deacetylase inhibitor valproic acid, on the expression of HLA class-I molecules and on the antigen-specific immune recognition of cervical cancer cells.

Methods

Cell lines C33A (HPV-), CaSki (HPV-16+) and MS751 (HPV-18+) were treated with hydralazine and valproic acid to assess the expression of HLA class-I molecules by flow cytometry and RT-PCR. Promoter methylation of HLA class-I -A, -B and C, was also evaluated by Methylation-Specific PCR. Primary cervical tumors of four HLA-A*0201 allele patients were typed for HPV and their CTL's stimulated in vitro with the T2 cell line previously loaded with 50 μM of the HPV peptides. Cytotoxicity of stimulated CTL's was assayed against Caski and MS751 cells pre-treated with hydralazine and valproic acid.

Results

Valproic acid and hydralazine/valproic acid up-regulated the constitutive HLA class-I expression as evaluated by flow cytometry and RT-PCR despite constitutive promoter demethylation at these loci. Hydralazine and valproic acid in combination but no IFN-gamma hyperacetylated histone H4 as evaluated by ChiP assay. The antigenic immune recognition of CaSki and MS751 cells by CTLs specific to HPV-16/18 E6 and E7-derived epitopes, was increased by VA and H/VA and the combination of H/VA/IFN-gamma.

Conclusion

These results support the potential use of hydralazine and valproic acid as an adjuvant for immune intervention in cervical cancer patients whenever clinical protocols based on tumor antigen recognition is desirable, like in those cases where the application of E6 and E7 based therapeutic vaccines is used.
Appendix
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Metadata
Title
Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid
Authors
María de Lourdes Mora-García
Alfonso Duenas-González
Jorge Hernández-Montes
Erick De la Cruz-Hernández
Enrique Pérez-Cárdenas
Benny Weiss-Steider
Edelmiro Santiago-Osorio
Vianney Francisco Ortíz-Navarrete
Víctor Hugo Rosales
David Cantú
Marcela Lizano-Soberón
Martha Patricia Rojo-Aguilar
Alberto Monroy-García
Publication date
01-06-2006
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2006
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-4-55

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