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Tissue transglutaminase constitutively activates HIF-1? promoter and nuclear factor-?B via a non-canonical pathway.

ABSTRACT: Constitutive activation of nuclear factor kappa B (NF-?B) 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-?B 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-?B. TG2-induced NF-?B binds the functional NF-?B binding site in hypoxia-inducible factor-1 (HIF-1?) promoter and results in its increased expression at transcription and protein levels even under normoxic conditions. TG2/NF-?B-induced HIF-1 was deemed essential for increased expression of some transcription repressors, like Zeb1, Zeb2, Snail, and Twist. Unlike tumor necrosis factor-alpha (TNF?), TG2 did not require I?B kinase (IKK) for NF-?B activation. Our data suggest that TG2 binds with I?B? 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-?B 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-?B) complex binds to the HIF-1 promoter and induced its transcriptional regulation. Inhibition of TG2 or p65/RelA also inhibited the HIF-1? expression and attenuated Zeb1, Zeb2, and Twist expression. To our knowledge, these findings show for the first time a direct link between TG2, NF-?B, and HIF-1?, demonstrating TG2's important role in cancer progression.

SUBMITTER: Kumar S

PROVIDER: S-EPMC3501523 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Tissue transglutaminase constitutively activates HIF-1α promoter and nuclear factor-κB via a non-canonical pathway.

Kumar Santosh S Mehta Kapil K

PloS one 20121119 11

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-ind ...[more]

PMID: 23185316

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Project description:Non-Hodgkin's lymphoma (NHL) is a cancer closely associated with immune function, and the tumor necrosis factor (TNF) G-308A promoter polymorphism, which influences immune function and regulation, was recently reported by the InterLymph Consortium to be associated with NHL risk. TNF signaling activates the nuclear factor-kappaB (NF-kappaB) canonical pathway, leading to transcriptional activation of multiple genes that influence inflammation and immune response. We hypothesized that, in addition to TNF signaling, common genetic variation in genes from the NF-kappaB canonical pathway may affect risk of NHL. We genotyped 54 single nucleotide polymorphisms (SNP) within TNF, lymphotoxin A LTA, and nine NF-kappaB genes from the canonical pathway (TNFRSF1A, TRADD, TRAF2, TRAF5, RIPK1, CHUK, IKBKB, NFKB1, and REL) in a clinic-based study of 441 incident cases and 475 frequency-matched controls. Tagging SNPs were selected from HapMap supplemented by putative functional SNPs for LTA/TNF. We used principal components and haplo.stats to model gene-level associations and logistic regression to model SNP-level associations. Compared with the wild-type (GG), the AA genotype for the TNF promoter polymorphism G-308A (rs1800629) was associated with increased risk of NHL [odds ratio (OR), 2.14; 95% confidence interval (95% CI), 0.94-4.85], whereas the GA genotype was not (OR, 1.00; 95% CI, 0.74-1.34). This association was similar for follicular lymphoma and diffuse large B-cell lymphoma. A previously reported LTA/TNF haplotype was also associated with NHL risk. In gene-level analysis of the NF-kappaB pathway, only NFKB1 showed a statistically significant association with NHL (P = 0.049), and one NFKB1 tagSNP (rs4648022) was associated with NHL risk overall (ordinal OR, 0.59; 95% CI, 0.41-0.84; Ptrend = 0.0037) and for each of the common subtypes. In conclusion, we provide additional evidence for the role of genetic variation in TNF and LTA SNPs and haplotypes with risk of NHL and also provide some of the first preliminary evidence for an association of genetic variation in NFKB1, a downstream target of TNF signaling, with risk of NHL.

Dataset Information

Tissue transglutaminase constitutively activates HIF-1? promoter and nuclear factor-?B via a non-canonical pathway.

Publications

Tissue transglutaminase constitutively activates HIF-1α promoter and nuclear factor-κB via a non-canonical pathway.

Similar Datasets

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