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

Seredinski, Sandra; Boos, Frederike; Günther, Stefan; Oo, James A.; Warwick, Timothy; Ponce, Judit Izquierdo; Lillich, Felix F; Proschak, Ewgenij; Knapp, Stefan; Gilsbach, Ralf; Pflüger‐Müller, Beatrice; Brandes, Ralf P.; Leisegang, Matthias

doi:10.1016/j.omtn.2022.01.016

Cited by 9 publications

(16 citation statements)

References 61 publications

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“…1J, S1C ). Conversely, the DNA topoisomerase and HIF-inhibitor acriflavine (ACF) [57] led to a decrease in LINC00607 expression, which was exacerbated under hypoxia ( Fig. 1K-M ).…”

Section: Resultsmentioning

confidence: 99%

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The endothelial-specific LINC00607 mediates endothelial angiogenic function

Boos

Warwick

et al. 2022

Preprint

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Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1.

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“…1J, S1C ). Conversely, the DNA topoisomerase and HIF-inhibitor acriflavine (ACF) [57] led to a decrease in LINC00607 expression, which was exacerbated under hypoxia ( Fig. 1K-M ).…”

Section: Resultsmentioning

confidence: 99%

“…The following RNA-Seq datasets used in this study originated from NCBI GEO: HUVEC treated with normoxia or hypoxia (GSE70330) [18]; ACF treatments of HUVEC under normoxia (GSE176555) or hypoxia (GSE186297) [57]; EndMT treatments of HUVEC and PAEC (GSE118446) [48].…”

Section: Publicly Available Datasetsmentioning

confidence: 99%

The endothelial-specific LINC00607 mediates endothelial angiogenic function

Boos

Warwick

et al. 2022

Preprint

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“…Proflavine changes the structure of the DNA strand and binds to topoisomerases I and II, loosening or splitting the double-stranded DNA and intercalating between adjacent layers of nucleotide pairs. 11 , 67 This leads to a series of mutations in the genetic material or apoptosis. Proflavine has been found to bind better to alternating purine–pyrimidine DNA sequences than ACF.…”

Section: Physical and Biological Properties Of Acriflavinementioning

confidence: 99%

Section: Physical and Biological Properties Of Acriflavinementioning

confidence: 99%

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Acriflavine, an Acridine Derivative for Biomedical Application: Current State of the Art

2022

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Acriflavine (ACF) has been known for years as an antibacterial drug. The identification of key oncogenic mechanisms has brought, in recent years, a significant increase in studies on ACF as a multipurpose drug that would improve the prognosis for cancer patients. ACF interferes with the expression of the hypoxia inducible factor, thus acting on metastatic niches of tumors and significantly enhancing the effects of other anticancer therapies. It has been recognized as the most potent HIF-1 inhibitor out of the 336 drugs approved by the FDA. This work presents up-to-date knowledge about the mechanisms of action of ACF and its related prodrug systems in the context of anticancer and SARS-CoV-2 inhibitory properties. It explains the multitask nature of this drug and suggests mechanisms of ACF’s action on the coronavirus. Other recent reports on ACF-based systems as potential antibacterial and antiviral drugs are also described.

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The endothelial-enriched lncRNA LINC00607 mediates angiogenic function

Boos

Warwick

et al. 2023

Basic Res Cardiol

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Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates, post-atherosclerotic cultured endothelial cells from patients and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1 to ultimately mediate angiogenesis.

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

Cited by 9 publications

References 61 publications

The endothelial-specific LINC00607 mediates endothelial angiogenic function

The endothelial-specific LINC00607 mediates endothelial angiogenic function

Acriflavine, an Acridine Derivative for Biomedical Application: Current State of the Art

The endothelial-enriched lncRNA LINC00607 mediates angiogenic function

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