Sandra Seredinski, Frederike Boos, Stefan Günther, James A. Oo, Timothy Warwick, Judit Izquierdo Ponce, Felix F. Lillich, Ewgenij Proschak, Stefan Knapp, Ralf Gilsbach, Beatrice Pflüger-Müller, Ralf Brandes, Matthias Leisegang
- 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 (RNA-seq), 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.
Metadaten| Author: | Sandra Seredinski, Frederike Boos, Stefan GüntherORCiD, James A. Oo, Timothy WarwickORCiDGND, Judit Izquierdo Ponce, Felix F. Lillich, Ewgenij ProschakORCiDGND, Stefan KnappORCiDGND, Ralf Gilsbach, Beatrice Pflüger-MüllerORCiDGND, Ralf BrandesORCiDGND, Matthias LeisegangORCiDGND |
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| URN: | urn:nbn:de:hebis:30:3-783364 |
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| DOI: | https://doi.org/10.1016/j.omtn.2022.01.016 |
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| ISSN: | 2162-2531 |
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| Parent Title (English): | Molecular Therapy : Nucleic Acids |
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| Publisher: | New York, NY |
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| Place of publication: | Nature Publ. Group |
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| Document Type: | Article |
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| Language: | English |
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| Date of Publication (online): | 2022/01/24 |
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| Date of first Publication: | 2022/01/24 |
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| Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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| Release Date: | 2024/08/19 |
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| Tag: | acriflavine; angiogenesis; chromatin; endothelial cells; hypoxia; long non-coding RNA; topoisomerase inhibitor |
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| Volume: | 27 |
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| Page Number: | 13 |
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| First Page: | 1023 |
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| Last Page: | 1035 |
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| Note: | Data availability
The datasets of normoxic experiments (ATAC-seq GSE176554, RNA-seq GSE176555) have been deposited as a superseries and are available at NCBI GEO with the accession number GSE176556.
The RNA-seq dataset under hypoxic conditions has been deposited and is available at NCBI GEO with the accession number GSE186297. |
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| Note: | Funding: DZHK, PostDoc Startup Grant 81X3200107 |
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| Note: | Funding: DFG Excellence Cluster Cardiopulmonary Institute (CPI) EXS2026, DFG Transregio TRR267 (TPA04 and TPA06), and SFB1039 |
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| Institutes: | Medizin |
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| Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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| Sammlungen: | Universitätspublikationen |
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| Licence (German): |  Creative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International |
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