Tumor necrosis factor ?-induced hypoxia-inducible factor 1?-?-catenin axis regulates major histocompatibility complex class I gene activation through chromatin remodeling.

ABSTRACT: Hypoxia-inducible factor 1? (HIF-1?) 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-1? is a pivotal link between inflammation and glioma progression, the role of tumor necrosis factor alpha (TNF-?)-induced inflammation in MHC-I gene regulation was investigated. A TNF-?-induced increase in MHC-I expression and transcriptional activation was concurrent with increased HIF-1?, ?F-??, and ?-catenin activities. While knockdown of HIF-1? and ?-catenin abrogated TNF-?-induced MHC-I activation, NF-?B had no effect. ?-Catenin inhibition abrogated HIF-1? activation and vice versa, and this HIF-1?-?-catenin axis positively regulated CREB phosphorylation. Increased CREB activation was accompanied by its increased association with ?-catenin and CBP. Chromatin immunoprecipitation revealed increased CREB enrichment at CRE/site ? on the MHC-I promoter in a ?-catenin-dependent manner. ?-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-?-induced MHC-I expression. ?-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-1?/?-catenin-dependent manner.

SUBMITTER: Ghosh S 

PROVIDER: S-EPMC3700138 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature