IRF3 and HIF hydroxylation by EGLN1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Wuhan Xiao
PROVIDER: PXD048667 | iProX | Thu Jan 18 00:00:00 GMT 2024
REPOSITORIES: iProX
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Project description:Hypoxia-inducible factor-1 (HIF-1) is a master regulator of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits PHD3 to PKM2 to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with hnRNPF to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly rescues their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
2021-01-19 | GSE159490 | GEO
Project description:Peritoneal metastasis (PM) is diagnosed in almost half of patients with advanced gastric cancer (GCa) and has a very poor prognosis. However, the molecular mechanisms of PM in GCa remain poorly understood. Here, we show that the elevated expression of RAR-related orphan receptor gamma (RORγ) in GCa tumors is a key driver of PM. RORγ drives GCa progression and metastasis by assembling a transcriptional complex with HIF-1α that regulates the expression of HIF-1α targets via recruitment of RNA polymerase II and p300. Mechanistically, RORγ hijacks HIF-1α to disrupt the interaction between HIF-1α and PHD3, leading to decreased HIF-1α hydroxylation, ubiquitylation and increased HIF-1α accumulation, nuclear translocation, and transactivation. RORγ antagonists block tumor growth and PM in multiple xenograft GCa models, and they effectively sensitize GCa tumors to chemotherapy in mice. Thus, our study uncovers a mechanism of RORγ-driven PM and offers a potential therapeutic option against advanced GCa.
2024-12-25 | GSE206444 | GEO
Project description:Peritoneal metastasis (PM) is diagnosed in almost half of patients with advanced gastric cancer (GCa) and has a very poor prognosis. However, the molecular mechanisms of PM in GCa remain poorly understood. Here, we show that the elevated expression of RAR-related orphan receptor gamma (RORγ) in GCa tumors is a key driver of PM. RORγ drives GCa progression and metastasis by assembling a transcriptional complex with HIF-1α that regulates the expression of HIF-1α targets via recruitment of RNA polymerase II and p300. Mechanistically, RORγ hijacks HIF-1α to disrupt the interaction between HIF-1α and PHD3, leading to decreased HIF-1α hydroxylation, ubiquitylation and increased HIF-1α accumulation, nuclear translocation, and transactivation. RORγ antagonists block tumor growth and PM in multiple xenograft GCa models, and they effectively sensitize GCa tumors to chemotherapy in mice. Thus, our study uncovers a mechanism of RORγ-driven PM and offers a potential therapeutic option against advanced GCa.
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Project description:Hypoxia Inducible Factor (HIF) prolyl hydroxylase domain (PHD) enzymes catalyse the posttranslational hydroxylation of conserved prolyl residues in the alpha-subunit of the HIF transcription factor. These modifications, which promote the degradation of HIF-alpha subunits by the pVHL E3 ligase complex and impart oxygen-dependent regulation of the HIF transcriptional response, have been extensively characterised at the molecular, cellular and organismal level. Since the discovery of the PHDs, a range of less well-characterised non-HIF substrates have been reported with the potential to confer oxygen-sensitivity to a diverse range of cellular processes. We sought to systematically compare all of the reported non-HIF substrates for their ability to support PHD-catalysed hydroxylation. We performed a comprehensive series of in vitro hydroxylation assays reacting synthetic peptides and full-length protein substrates generated by in vitro transcription and translation with purified recombinant enzyme preparations. Prolyl hydroxylation was assayed directly by mass spectrometry and radiochemical assay for hydroxyproline. Both methods enabled quantitative appraisal of enzyme-catalysed hydroxylation, with liquid chromatography mass spectrometry methods employing NMR-quantified peptide standards to calibrate retention time signatures and determine ionisation efficiencies for each target peptide. Using these approaches we assayed hydroxylation on 23 different proteins. Surprisingly, we did not detect measurable hydroxylation on any of the reported non-HIF substrates using either method. In contrast, control assays with HIF1-alpha substrate supported high stoichiometry (typically >90%) hydroxylation. Our findings suggest that PHD substrates are more restricted than has been reported.
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Project description:Mutational inactivation of VHL is the earliest genetic event in the majority of ccRCCs, leading to activation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCCs and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Using an autochthonous ccRCC model, we show genetically that Hif1a is necessary for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are necessary for the clear cell phenotype. Transcriptomic and proteomic analyses revealed that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. Deficiency of HIF-2α increased CD8+ T cell infiltration and activation. These studies reveal different functions of HIF-1α and HIF-2α in ccRCC. SIGNIFICANCE The roles of HIF-1α and HIF-2α in ccRCC pathogenesis remain unclear. Using a mouse genetic approach we show that HIF-1α but not HIF-2α is important for tumour formation, contrary to predictions from studies of human ccRCC. We show that HIF-1α and HIF-2α transcriptionally regulate different aspects of metabolism and identify HIF-2α as a suppressor of immune cell infiltration and activation.
2020-07-02 | PXD016630 | Pride
Project description:NAA10 is the major human N-terminal acetyltransferase (NAT). The KAT activity of NAA10 towards hypoxia-inducible factor 1α (HIF-1α) was recently reported to depend on the hydroxylation at Trp38 of NAA10 by factor inhibiting HIF-1α (FIH). As a consequence, Trp38 hydroxylation status was proposed to act as a general NAA10-switch between its NAT and KAT state. We attempted to quantify the degree of hydroxylation of NAA10. We could not detect any hydroxylation of Trp38 of NAA10 in several human cell lines.
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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-1α in colon, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-1α+/+, Hif-1αLSL/LSL mice. Background & Aims: The progression and growth of solid tumors leads to a state where tumors outgrow their capacity for efficient oxygenation and nutrient uptake and an increase in tumor hypoxia. Tumor hypoxic response is mediated by hypoxia-inducible factor (HIF)-1a and HIF-2a. These transcription factors regulate a battery of genes that are critical for tumor oxygenation, tumor metabolism, and cell proliferation and survival. Therefore, inhibitors of HIF have been sought for as anti-neoplastic agents in several different kinds of cancers. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1a is beneficial, and can reduce intestinal inflammation. The efficacy of pharmacological agents that chronically activate HIF-1a are decreased due to the tumorigenic potential of HIF. However, recent advance in understanding HIF signaling have identified mechanisms, which could allow for isoform specific activators. Activation of HIF-2a increases colon carcinogenesis and progression in mouse models. However, the role of chronic HIF-1a activation is unclear in the progression in colon cancer. The present data demonstrates that activation of HIF-1a in epithelial cells does not increase colon carcinogens or progression in two mouse models of colon cancer, and provides the proof of principle that HIF-1a activation maybe safe as therapies for inflammatory bowel disease. Global gene expression profiling in colon RNAs isolated from 6- to 8-week-old Hif-1α+/+ (n=5, Shah 019) and Hif-1αLSL/LSL (n=5, Shah 020).
2014-05-14 | E-GEOD-55915 | biostudies-arrayexpress
Project description:Analysis of Huh-7 hepatocarcinoma cell line depleted of NDRG3 or HIF-1α under hypoxic condition. HIF-1α and NDRG3 have distinct functions in hypoxia responses. Results provide insight into molecular basis of HIF-independent signaling in the development and progression of hypoxic tumors Gene expression profiles of Huh-7 cells stably expressing NDRG3-shRNA or HIF-1α-shRNA under normoxia were compared to gene expression profiles of Huh-7 stable cells under hypoxia for 6, 12 and 24 hours.
2015-07-24 | E-GEOD-55212 | biostudies-arrayexpress
Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).
2013-02-28 | E-GEOD-43416 | biostudies-arrayexpress
Project description:Hypoxia inducible factor-1α (HIF-1α) is a critical transcription factor for the hypoxic response, angiogenesis, normal hematopoietic stem cell regulation, and cancer development. Importantly, HIF-1α is also a key regulator for immune cell activation. In order to determine whether HIF-1α is sufficient for developing MDS phenotypes, we generated blood specific inducible HIF-1α transgenic mice. Using Vav1-Cre/Rosa26-loxP-Stop-loxP (LSL) rtTA driver, stable HIF-1α can be induced in a doxycycline administration dependent manner. After induction, HIF-1α-induced mice developed thrombocytopenia, leukocytopenia, macrocytic anemia, and multi-lineage dysplasia. We also found activation of both innate and adaptive immunity in HIF-1α- induced mice compared to those from control mice. Taken together, these data suggest that HIF-1α is sufficient to trigger a variety of key MDS features
2018-12-25 | GSE83988 | GEO