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Characterization of a gene expression biomarker predictive of hypoxia-inducible factor-1 modulation

ABSTRACT: We describe here a gene expression biomarker that can accurately identify chemicals and genetic conditions that perturb hypoxia-inducible factor-1 (HIF-1), a transcription factor critical for the cellular response to hypoxia involved in the pathophysiology of cancer, inflammation, and ischemia. The HIF-1 biomarker genes were identified from transcript profiles in a variety of human cell lines after hypoxia as well as genetic knockdown of the HIF1A gene. The HIF-1 biomarker of 122 genes was found to be enriched for: genes bound by HIF-1 using ChIP-Seq, metabolic pathways regulated by HIF-1 (e.g., gluconeogenesis). Using Ingenuity Pathway Analysis, HIF-1 was the top predicted regulator of the genes. The biomarker could identify activation of HIF-1 by overexpression of the HIF1A gene or suppression of the negative regulator, von-Hipple Lindau (VHL) gene; suppression of HIF-1 occurred by inhibition of the expression of HIF1A or the heterodimer partner aryl hydrocarbon receptor nuclear translocator (ARNT). The biomarker was specific for HIF-1 activation, as activation or suppression of the HIF-2 gene was not detected by the biomarker. Using a reference chemical set with 180 positives and 45 negatives, the balanced accuracy of the HIF-1 biomarker to identify activation was 94.1%. An in-silico screen of a gene expression compendium identified hundreds of potential activators. Eleven of these were selected for verification and all were found to activate HIF-1 biomarker genes in wild-type but not HIF1A-null cells. The HIF-1 biomarker will be a useful tool to identify environmentally relevant chemicals that affect HIF-1 in high-throughput transcriptomics screening studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291564 | GEO | 2025/03/14

REPOSITORIES: GEO

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Project description:The activation of the transcription factor Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small-molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high throughput screen led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations but did not affect expression levels of genes outside of the HIF-1 pathway. Lead structure BAY 87-2243 was found to inhibit HIF-1Î± protein accumulation under hypoxic conditions in NSCLC cell line H460 but had no effect on HIF-1Î± protein accumulation and HIF target gene expression in RCC4 cells lacking VHL activity or in H460 cells after inhibition of HIF prolyl hydroxylase activity. BAY 87-2243 had no effect on HIF-Î±-mRNA levels. Antitumor activity of BAY 87-2243 and suppression of HIF-1 target gene expression in vivo was demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial production of reactive oxygen species (ROS) by blocking complex I activity but has no effect on complex III activity. Lowering of mitochondrial ROS production to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors. We used microarrays to detail the global programme of gene expression that is induced in NSCLC cell line H460 upon hypoxia (16 h incubation at 1 % pO2) and evaluated a dose-dependent effect of our HIF-1-pathway inhibitor BAY 87-2243 on genes tthat are affected by hypoxia. Specificity of BAY 87-2243 for the suppression of HIF-1-mediated gene transcription on a genome-wide scale was evaluated by microarray hybridizations using Affymetrix GeneChip Human Gene 1.0 ST arrays. RNA from normoxic H460 cells and from hypoxic H460 cells incubated with 1, 10 and 100 nM BAY 87-2243 respectively was subjected to array hybridization. Of those 30 genes that were most strongly suppressed by 100 nM BAY 87-2243 in hypoxic H460 cells compared to DMSO-treated hypoxic H460 cells, virtually all of them are induced by prior hypoxia and most of these genes have been described in the literature as HIF-1 target genes

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Characterization of a gene expression biomarker predictive of hypoxia-inducible factor-1 modulation

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