Tumor necrosis factor α-induced hypoxia-inducible factor 1α-β-catenin axis regulates major histocompatibility complex class I gene activation through chromatin remodeling.
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, ÎF-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.
Mesh Terms:
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Binding, Competitive, CCAAT-Binding Factor, Cell Line, Tumor, Chromatin Assembly and Disassembly, Cyclic AMP Response Element-Binding Protein, DNA Helicases, DNA-Binding Proteins, Gene Expression, Genes, MHC Class I, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, NF-kappa B, Nuclear Proteins, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Protein Processing, Post-Translational, Regulatory Factor X Transcription Factors, Response Elements, Transcription Factor 4, Transcription Factors, Transcriptional Activation, Tumor Necrosis Factor-alpha, beta Catenin
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Binding, Competitive, CCAAT-Binding Factor, Cell Line, Tumor, Chromatin Assembly and Disassembly, Cyclic AMP Response Element-Binding Protein, DNA Helicases, DNA-Binding Proteins, Gene Expression, Genes, MHC Class I, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, NF-kappa B, Nuclear Proteins, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Protein Processing, Post-Translational, Regulatory Factor X Transcription Factors, Response Elements, Transcription Factor 4, Transcription Factors, Transcriptional Activation, Tumor Necrosis Factor-alpha, beta Catenin
Mol. Cell. Biol.
Date: Jul. 01, 2013
PubMed ID: 23671189
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