Tissue transglutaminase constitutively activates HIF-1α promoter and nuclear factor-κB via a non-canonical pathway.
Constitutive activation of nuclear factor kappa B (NF-κB) has been linked with carcinogenesis and cancer progression, including metastasis, chemoresistance, and radiation resistance. However, the molecular mechanisms that result in constitutive activation of NF-κB are poorly understood. Here we show that chronic expression of the pro-inflammatory protein tissue transglutaminase (TG2) reprograms ... the transcription regulatory network in epithelial cells via constitutive activation of NF-κB. TG2-induced NF-κB binds the functional NF-κB binding site in hypoxia-inducible factor-1 (HIF-1α) promoter and results in its increased expression at transcription and protein levels even under normoxic conditions. TG2/NF-κB-induced HIF-1 was deemed essential for increased expression of some transcription repressors, like Zeb1, Zeb2, Snail, and Twist. Unlike tumor necrosis factor-alpha (TNFα), TG2 did not require IκB kinase (IKK) for NF-κB activation. Our data suggest that TG2 binds with IκBα and results in its rapid degradation via a non-proteasomal pathway. Importantly, the catalytically inactive (C277S) mutant form of TG2 was as effective as was wild-type TG2 in activating NF-κB and inducing HIF-1 expression. We also found that TG2 interacted with p65/RelA protein, both in the cytosolic and the nuclear compartment. The TG2/p65(NF-κB) complex binds to the HIF-1 promoter and induced its transcriptional regulation. Inhibition of TG2 or p65/RelA also inhibited the HIF-1α expression and attenuated Zeb1, Zeb2, and Twist expression. To our knowledge, these findings show for the first time a direct link between TG2, NF-κB, and HIF-1α, demonstrating TG2's important role in cancer progression.
Mesh Terms:
Biocatalysis, Cell Line, Chromatin Immunoprecipitation, Cross-Linking Reagents, Down-Regulation, GTP-Binding Proteins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, I-kappa B Kinase, I-kappa B Proteins, Models, Biological, NF-KappaB Inhibitor alpha, NF-kappa B, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Protein Binding, Proteolysis, Repressor Proteins, Signal Transduction, Transcription, Genetic, Transglutaminases
Biocatalysis, Cell Line, Chromatin Immunoprecipitation, Cross-Linking Reagents, Down-Regulation, GTP-Binding Proteins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, I-kappa B Kinase, I-kappa B Proteins, Models, Biological, NF-KappaB Inhibitor alpha, NF-kappa B, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Protein Binding, Proteolysis, Repressor Proteins, Signal Transduction, Transcription, Genetic, Transglutaminases
PLoS ONE
Date: Nov. 28, 2012
PubMed ID: 23185316
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