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  DNA topoisomerase inhibition with the HIF inhibitor acriflavine promotes transcription of lncRNAs in endothelial cells

Seredinski, S., Boos, F., Guenther, S., Oo, J. A., Warwick, T., Ponce, J. I., et al. (2022). DNA topoisomerase inhibition with the HIF inhibitor acriflavine promotes transcription of lncRNAs in endothelial cells. MOLECULAR THERAPY-NUCLEIC ACIDS, 27, 1023-1035. doi:10.1016/j.omtn.2022.01.016.

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 Creators:
Seredinski, Sandra, Author
Boos, Frederike, Author
Guenther, Stefan1, Author              
Oo, James A.2, Author              
Warwick, Timothy2, Author              
Ponce, Judit Izquierdo, Author
Lillich, Felix F., Author
Proschak, Ewgenij, Author
Knapp, Stefan, Author
Gilsbach, Ralf, Author
Pflueger-Mueller, Beatrice, Author
Brandes, Ralf P., Author
Leisegang, Matthias S., Author
Affiliations:
1Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591695              
2IMPRS, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_3242057              

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 Abstract: The transcription factor hypoxia-inducible factor 1 (HIF1) is an important driver of cancer and is therefore an attractive drug target. Acriflavine (ACF) has been suggested to inhibit HIF1, but its mechanism of action is unknown. Here we investigated the interaction of ACF with DNA and long non-coding RNAs (lncRNAs) and its function in human endothelial cells. ACF promoted apoptosis and reduced proliferation, network formation, and angiogenic capacity. It also induced changes in gene expression, as determined by RNA sequencing (RNAseq), which could not be attributed to specific inhibition of HIF1. A similar response was observed in murine lung endothelial cells. Although ACF increased and decreased a similar number of protein-coding genes, lncRNAs were preferentially upregulated under normoxic and hypoxic conditions. An assay for transposase accessibility with subsequent DNA sequencing (ATAC-seq) demonstrated that ACF induced strong changes in chromatin accessibility at lncRNA promoters. Immunofluorescence showed displacement of DNA:RNA hybrids. Such effects might be due to ACF-mediated topoisomerase inhibition, which was indeed the case, as reflected by DNA unwinding assays. Comparison with other acridine derivatives and topoisomerase inhibitors suggested that the specific function of ACF is an effect of acridinium-class compounds. This study demonstrates that ACF inhibits topoisomerases rather than HIF specifically and that it elicits a unique expression response of lncRNAs.

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 Dates: 2022-01-252022-03-08
 Publication Status: Published in print
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 Identifiers: ISI: 000766667300004
DOI: 10.1016/j.omtn.2022.01.016
PMID: 35228897
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Title: MOLECULAR THERAPY-NUCLEIC ACIDS
Source Genre: Journal
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Pages: - Volume / Issue: 27 Sequence Number: - Start / End Page: 1023 - 1035 Identifier: ISSN: 2162-2531