Factor inhibiting HIF (FIH) promotes lung cancer progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA914705 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22845587_1.fastq.gz | Fastqsanger.gz | |||
| SRR22845587_2.fastq.gz | Fastqsanger.gz | |||
| SRR22845588_1.fastq.gz | Fastqsanger.gz | |||
| SRR22845588_2.fastq.gz | Fastqsanger.gz | |||
| SRR22845589_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:Factor-inhibiting HIF (FIH) is an asparagine hydroxylase that acts on hypoxia-inducible factors (HIFs) to control cellular adaptation to hypoxia. FIH is expressed in several tumor types, but its impact in tumor progression remains largely unexplored. We observed that FIH was expressed on human lung cancer tissue. Deletion of FIH in mouse and human lung cancer cells resulted in an increased glycolytic metabolism, consistent with increased HIF activity. FIH-deficient lung cancer cells exhibited decreased proliferation. Analysis of RNA-Seq data confirmed changes in the cell cycle and survival and revealed molecular pathways that were dysregulated in the absence of FIH, including the upregulation of angiomotin (Amot), a key component of the Hippo tumor suppressor pathway. We show that FIH-deficient tumors were characterized by higher immune infiltration of NK and T cells compared with FIH competent tumor cells. In vivo studies demonstrate that FIH deletion resulted in reduced tumor growth and metastatic capacity. Moreover, high FIH expression correlated with poor overall survival in non-small cell lung cancer (NSCLC). Our data unravel FIH as a therapeutic target for the treatment of lung cancer.
2023-11-08 | GSE221505 | GEO
Project description:T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much of this adaptation, and thus regulate many aspects of T cell activation and function. The HIFs are in turn regulated by oxygen-dependent hydroxylases: both the prolyl hydroxylases (PHDs) which interact with the VHL tumor suppressor and control HIF turnover, and the asparaginyl hydroxylase known as the Factor inhibiting HIF (FIH), which modulates HIF transcriptional activity. To determine the role of this latter factor in T cell function, we generated T cell-specific FIH knockout mice. We found that FIH regulates T cell fate and function in a HIF-dependent manner and show that the effects of FIH activity occur predominantly at physiological oxygen concentrations. T cell-specific loss of FIH boosts T cell cytotoxicity, augments T cell expansion in vivo, and improves anti-tumor activity in mice. Specifically inhibiting FIH in T cells may therefore represent a promising strategy for cancer immunotherapy.
2023-06-14 | GSE234381 | GEO
Project description:O-GlcNAc transferase (OGT) has been reported to participate in the development of various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, we found that OGT was upregulated in ccRCC compared with paired nontumor renal tissues and was associated with worse survival. Moreover, OGT promoted the proliferation, clone formation, and invasive abilities of VHL-mutated ccRCC cells. Mechanistically, OGT promoted the expression of hypoxia-inducible factor-2α (HIF-2α) (the main driver of the clear cell phenotype) by repressing ubiquitin‒proteasome system-mediated degradation. Interestingly, the OGT/HIF-2α axis confers ccRCC sensitivity to ferroptosis, rendering it vulnerable. In conclusion, OGT promotes the progression of VHL-mutated ccRCC by inhibiting the degradation of HIF-2α. On the other hand, the OGT/HIF-2α axis renders ccRCC vulnerable to ferroptosis, suggesting that ferroptosis inducers are a promising therapy for patients with upregulated OGT and mutated VHL ccRCC.
2023-04-29 | GSE230386 | GEO
Project description:The aspariginyl-hydroxylase activity of Factor Inhibiting HIF (FIH) is a key regulator of the transcriptional activity of the hypoxia inducible factor. FIH also catalyses the hydroxylation of asparaginyl- and other-residues in ankyrin repeat domain (ARD) containing proteins, including Apoptosis stimulating of p53 (ASPP) protein family members. ASPP2 is reported to undergo a single FIH catalysed hydroxylation at Asn-986. We report biochemical and crystallographic evidence showing FIH can catalyse the unprecedented post-translational hydroxylation of both asparaginyl-residues in “VNVN” and related motifs of ankyrin repeat domains in apoptosis-stimulating of p53 (ASPP) proteins (i.e. ASPP1, ASPP2 and iASPP) and the related ASB11 and p18-INK4C proteins. The results extend the substrate scope of FIH catalysis and may have implications for its role in the hypoxic response and, ASPP protein function.
2022-08-11 | PXD017278 | Pride
Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive Hypoxia Inducible Factor (HIF) transcriptional regulators HIF-1α and HIF-2α are overexpressed in many human NSCLCs, and constitutive HIF-2α activity can promote murine lung tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate the consequences of inhibiting HIF activity in lung cancers, we deleted Hif-1α or Hif-2α in an established KrasG12D-driven murine NSCLC model. Deletion of Hif-1α had no obvious effect on tumor growth, whereas Hif-2α deletion resulted in an unexpected increase in tumor burden that correlated with reduced expression of the candidate tumor suppressor gene Scgb3a1 (HIN-1). Here, we identify Scgb3a1 as a direct HIF-2α target gene, and demonstrate that HIF-2α regulates Scgb3a1 expression and tumor formation in human KrasG12D-driven NSCLC cells. AKT pathway activity, reported to be repressed by Scgb3a1, was enhanced in HIF-2α deficient human NSCLC cells and xenografts. Finally, a direct correlation between HIF-2α and SCGB3a1 expression was observed in approximately 70% of human NSCLC samples analyzed. These data suggest that whereas HIF-2α overexpression can contribute to NSCLC progression, therapeutic inhibition of HIF-2α below a critical threshold may paradoxically promote tumor growth by reducing expression of tumor suppressor genes, including Scgb3a1. RNA was isolated from tumors of experimental (Hif2alpha deficient) mice and control mice (seven for each group).
2010-07-29 | E-GEOD-22575 | biostudies-arrayexpress
Project description:The Factor Inhibiting HIF regulates T cell differentiation and anti-tumor efficacy
| PRJNA981153 | ENA
Project description:We describe a unique regulation of the succinylacetone/PHD2/HIF-1α axis by a metabolic enzyme GSTZ1. The total RNA was isolated from HepG2 cells stably transfected with or without GSTZ1-KO and analyzed using RNA-seq. Our work demonstrates that GSTZ1-deficient promotes HCC angiogenesis through stabilizing HIF-1α due to succinylacetone accumulation. In addition, the combination of targeting HIF-1α and PD-L1 could limit tumorigenesis and progression for Gstz1-/-mice, thus providing a potential target for HCC therapy.
2023-11-06 | GSE192760 | GEO
Project description:IRF2BP2 promotes neuroblastoma progression
| PRJNA990742 | ENA
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:Alternative RNA splicing analysis in Hep3B cell cultured under 21% (N1,3,5) or 1.2% (H2,4,6) oxygen Hypoxia is a common characteristic of many solid tumors. The hypoxic microenvironment stabilizes hypoxia-inducible transcription factor 1? (HIF1?) and 2? (HIF2?) to activate gene transcription, which promotes tumor cell survival. 95% of human genes are alternatively spliced, producing RNA isoforms that code functionally distinct proteins. Thus, effective hypoxia response requires increased HIF target gene transcription as well as proper RNA splicing of these HIF target genes. However, it is unclear if and how hypoxia regulates RNA splicing of HIF target genes. This study determined the effects of hypoxia on alternative splicing (AS) of HIF and non-HIF target genes in Hep3B cells and characterized the role of HIF in regulating AS of HIF induced genes. The results indicated that hypoxia generally promotes exon inclusion for hypoxia-induced, but reduces exon inclusion for hypoxia reduced genes. Mechanistically, HIF activity, but not hypoxia per se is found to be necessary and sufficient to increase exon inclusion of several HIF target genes including pyruvate dehydrogenase kinase 1 (PDK1). PDK1 splicing reporters confirmed that transcriptional activation by HIF is sufficient to increase exon inclusion of PDK1 splicing reporter. In contrast, transcriptional activation of the PDK1 minigene by other transcription factor in the absence of endogenous HIF target gene activation fails to alter PDK1 RNA splicing, demonstrating a novel role of HIF target gene(s) in regulating RNA splicing of HIF target genes. Implications:This study demonstrates a novel function of HIF in regulating RNA splicing of HIF target genes. We analyzed total RNA from Hep3B cells cultured under 21% (N1,3,5) or 1.2% (H2,4,6) oxygen using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Altanalyze software version 2.0.7. Techinical replicates were performed for Nx and Hx treated Hep3B cells
2014-05-14 | E-GEOD-57613 | biostudies-arrayexpress