Mouillot Gaël, Marcou Céline, Rousseau Philippe, Rouas-Freiss Nathalie, Carosella Edgardo D, Moreau Philippe
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.
Int J Cancer. 2005 Mar 1;113(6):928-36. doi: 10.1002/ijc.20682.
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.
HLA - G分子的组织分布比最初报道的滋养层细胞中的分布更为广泛。基于大量研究，HLA - G也在恶性肿瘤中表达，并参与肿瘤免疫逃逸。HLA - G基因调控机制不同于经典的HLA I类基因，涉及表观遗传过程。在此，我们提供了关于DNA去甲基化对HLA - G激活影响的更多证据。我们还在两种细胞模型中分析了HLA - G的5'调控区，即黑色素瘤（FON、M8）和绒毛膜癌（JEG - 3、JAR），这两种细胞模型要么表达HLA - G转录本，要么不表达。数据强烈表明，HLA - G由于起始密码子上游450 bp的5'调控区内CpG位点的高甲基化而沉默，而去甲基化后则被激活。这一结果与该区域内组蛋白的乙酰化状态以及位于 - 1.2 kb处的假定基因座控制区相关。在表观遗传癌症治疗中应考虑顺式作用的表观遗传变化以及去甲基化剂在处理后至少5天激活HLA - G表达这一事实。
