Three-dimensional CRISPR screening reveals epigenetic interaction with anti-angiogenic therapy.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
15 07 2021
15 07 2021
Historique:
received:
14
12
2020
accepted:
23
06
2021
entrez:
16
7
2021
pubmed:
17
7
2021
medline:
12
11
2021
Statut:
epublish
Résumé
Angiogenesis underlies development, physiology and pathogenesis of cancer, eye and cardiovascular diseases. Inhibiting aberrant angiogenesis using anti-angiogenic therapy (AAT) has been successful in the clinical treatment of cancer and eye diseases. However, resistance to AAT inevitably occurs and its molecular basis remains poorly understood. Here, we uncover molecular modifiers of the blood endothelial cell (EC) response to a widely used AAT bevacizumab by performing a pooled genetic screen using three-dimensional microcarrier-based cell culture and CRISPR-Cas9. Functional inhibition of the epigenetic reader BET family of proteins BRD2/3/4 shows unexpected mitigating effects on EC survival and/or proliferation upon VEGFA blockade. Moreover, transcriptomic and pathway analyses reveal an interaction between epigenetic regulation and anti-angiogenesis, which may affect chromosomal structure and activity in ECs via the cell cycle regulator CDC25B phosphatase. Collectively, our findings provide insight into epigenetic regulation of the EC response to VEGFA blockade and may facilitate development of quality biomarkers and strategies for overcoming resistance to AAT.
Identifiants
pubmed: 34267311
doi: 10.1038/s42003-021-02397-3
pii: 10.1038/s42003-021-02397-3
pmc: PMC8282794
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Bevacizumab
2S9ZZM9Q9V
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
878Informations de copyright
© 2021. The Author(s).
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