HLA-G gene activation in tumor cells involves cis-acting epigenetic changes.
The tissue distribution of HLA-G molecules is broader than originally reported in trophoblastic cells. On the basis of numerous studies, HLA-G is also expressed in malignant tumors and involved in tumor immune escape. The mechanisms of HLA-G gene regulation differ from those of classical HLA class I genes and involve epigenetic processes. Here, we provide additional evidence on the influence of DNA demethylation on HLA-G activation. We also analyze the 5' regulatory region of HLA-G in 2 cellular models, melanoma (FON, M8) and choriocarcinoma (JEG-3, JAR), either expressing HLA-G transcripts or not. The data strongly suggest that HLA-G is silenced as a result of CpG site hypermethylation within a 5' regulatory region encompassing 450 bp upstream of the start codon, whereas it is activated upon demethylation. This result correlates with the acetylation status of histones within this region and the putative locus control region located at -1.2 kb. cis-acting epigenetic changes and the fact that demethylating agents activate HLA-G expression at least 5 days following treatment should be taken into account in epigenetic cancer therapies.
Mouillot
Gaël
G
Commissariat í l'Energie Atomique, Service de Recherches en Hémato-Immunologie, Direction des Sciences du Vivant/Département de Recherche Medicale, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
Marcou
Céline
C
Rousseau
Philippe
P
Rouas-Freiss
Nathalie
N
Carosella
Edgardo D
ED
Moreau
Philippe
P
D002051:Burkitt Lymphoma / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D017930:Genes, Reporter; D005910:Glioma / Q000235:genetics / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D017931:DNA Primers; D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I