title: Tumor necrosis factor α-induced hypoxia-inducible factor 1α-β-catenin axis regulates major histocompatibility complex class I gene activation through chromatin remodeling.
abstract: Hypoxia-inducible factor 1α (HIF-1α) plays a crucial role in the progression of glioblastoma multiforme tumors, which are characterized by their effective immune escape mechanisms. As major histocompatibility complex class I (MHC-I) is involved in glioma immune evasion and since HIF-1α is a pivotal link between inflammation and glioma progression, the role of tumor necrosis factor alpha (TNF-α)-induced inflammation in MHC-I gene regulation was investigated. A TNF-α-induced increase in MHC-I expression and transcriptional activation was concurrent with increased HIF-1α, ΝF-κΒ, and β-catenin activities. While knockdown of HIF-1α and β-catenin abrogated TNF-α-induced MHC-I activation, NF-κB had no effect. β-Catenin inhibition abrogated HIF-1α activation and vice versa, and this HIF-1α-β-catenin axis positively regulated CREB phosphorylation. Increased CREB activation was accompanied by its increased association with β-catenin and CBP. Chromatin immunoprecipitation revealed increased CREB enrichment at CRE/site α on the MHC-I promoter in a β-catenin-dependent manner. β-Catenin replaced human Brahma (hBrm) with Brg1 as the binding partner for CREB at the CRE site. The hBrm-to-Brg1 switch is crucial for MHC-I regulation, as ATPase-deficient Brg1 abolished TNF-α-induced MHC-I expression. β-Catenin also increased the association of MHC-I enhanceosome components RFX5 and NF-YB at the SXY module. CREB acts as a platform for assembling coactivators and chromatin remodelers required for MHC-I activation in a HIF-1α/β-catenin-dependent manner.
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Sadashib
authors.initials: S
authors.lastname: Ghosh
authors.forename: Arkoprovo
authors.initials: A
authors.lastname: Paul
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001667:Binding, Competitive; D023081:CCAAT-Binding Factor / Q000378:metabolism; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D005805:Genes, MHC Class I; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D000071701:Regulatory Factor X Transcription Factors; D020218:Response Elements; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D023081:CCAAT-Binding Factor; C115163:CREB1 protein, human; C495270:CTNNB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; C492063:NFYB protein, human; D009687:Nuclear Proteins; C093524:RFX5 protein, human; D000071701:Regulatory Factor X Transcription Factors; C084011:SMARCA2 protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; C084108:SMARCA4 protein, human; D004265:DNA Helicases