TY  - JOUR
A1  - Seredinski, Sandra
A1  - Boos, Frederike
A1  - Günther, Stefan
A1  - Oo, James A.
A1  - Warwick, Timothy
A1  - Izquierdo Ponce, Judit
A1  - Lillich, Felix F.
A1  - Proschak, Ewgenij
A1  - Knapp, Stefan
A1  - Gilsbach, Ralf
A1  - Pflüger-Müller, Beatrice
A1  - Brandes, Ralf
A1  - Leisegang, Matthias
T1  - DNA topoisomerase inhibition with the HIF inhibitor acriflavine promotes transcription of lncRNAs in endothelial cells
T2  - Molecular Therapy : Nucleic Acids
N2  - 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.
KW  - long non-coding RNA
KW  - endothelial cells
KW  - angiogenesis
KW  - chromatin
KW  - topoisomerase inhibitor
KW  - hypoxia
KW  - acriflavine
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/78336
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-783364
SN  - 2162-2531
N1  - 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.
N1  - Funding: DZHK, PostDoc Startup Grant 81X3200107
N1  - Funding: DFG Excellence Cluster Cardiopulmonary Institute (CPI) EXS2026, DFG Transregio TRR267 (TPA04 and TPA06), and SFB1039
VL  - 27
SP  - 1023
EP  - 1035
PB  - New York, NY
CY  - Nature Publ. Group
ER  -