title: Hypoxia inducible factor-1 mediates the expression of the immune checkpoint HLA-G in glioma cells through hypoxia response element located in exon 2.
abstract: HLA-G is an immune checkpoint molecule with specific relevance in cancer immunotherapy. It was first identified in cytotrophoblasts, protecting the fetus from maternal rejection. HLA-G tissue expression is very restricted but induced in numerous malignant tumors such as glioblastoma, contributing to their immune escape. Hypoxia occurs during placenta and tumor development and was shown to activate HLA-G. We aimed to elucidate the mechanisms of HLA-G activation under conditions combining hypoxia-mimicking treatment and 5-aza-2'deoxycytidine, a DNA demethylating agent used in anti-cancer therapy which also induces HLA-G. Both treatments enhanced the amount of HLA-G mRNA and protein in HLA-G negative U251MG glioma cells. Electrophoretic Mobility Shift Assays and luciferase reporter gene assays revealed that HLA-G upregulation depends on Hypoxia Inducible Factor-1 (HIF-1) and a hypoxia responsive element (HRE) located in exon 2. A polymorphic HRE at -966 bp in the 5'UT region may modulate the magnitude of the response mediated by the exon 2 HRE. We suggest that therapeutic strategies should take into account that HLA-G expression in response to hypoxic tumor environment is dependent on HLA-G gene polymorphism and DNA methylation state at the HLA-G locus.
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.|Lebanese University, School of Medicine, Hadath, Lebanon.
authors: Layale
authors: L
authors: Yaghi
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors: Isabelle
authors: I
authors: Poras
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.|Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, IEP/SCBH, Belo Horizonte, Minas Gerais, Brasil.
authors: Renata T
authors: RT
authors: Simoes
authors: Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors: Eduardo A
authors: EA
authors: Donadi
authors: Centre d'Etude du Polymorphisme Humain, Fondation Jean-Dausset, Laboratory for Functional Genomics, Paris, France.|Commissariat à l'Energie Atomique et aux Energies Alternatives, Centre National de Genotypage, Laboratory for Epigenetics and Environment, Evry, France.
authors: Jörg
authors: J
authors: Tost
authors: Centre d'Etude du Polymorphisme Humain, Fondation Jean-Dausset, Laboratory for Functional Genomics, Paris, France.
authors: Antoine
authors: A
authors: Daunay
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.|Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
authors: Bibiana Sgorla
authors: BS
authors: de Almeida
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors: Edgardo D
authors: ED
authors: Carosella
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors: Philippe
authors: P
authors: Moreau
mesh_terms: D020121:5' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D005091:Exons; D005805:Genes, MHC Class I; D005910:Glioma / Q000276:immunology*; D059951:HLA-G Antigens / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007107:Immune System; D009361:Neoplasm Invasiveness; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D020218:Response Elements; D015533:Transcriptional Activation
chemical_list: D020121:5' Untranslated Regions; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D059951:HLA-G Antigens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000077209:Decitabine; D001374:Azacitidine
keywords: HIF-1; HLA-G; exon 2 HRE; glioma