title: Tissue transglutaminase constitutively activates HIF-1α promoter and nuclear factor-κB via a non-canonical pathway.
abstract: 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.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Kapil
authors.initials: K
authors.lastname: Mehta
mesh_terms: D055162:Biocatalysis; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D003432:Cross-Linking Reagents / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D019204:GTP-Binding Proteins; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012097:Repressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex; D019204:GTP-Binding Proteins