A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1.
Journal
RSC chemical biology
ISSN: 2633-0679
Titre abrégé: RSC Chem Biol
Pays: England
ID NLM: 101768727
Informations de publication
Date de publication:
06 Apr 2022
06 Apr 2022
Historique:
received:
26
04
2021
accepted:
04
02
2022
entrez:
20
4
2022
pubmed:
21
4
2022
medline:
21
4
2022
Statut:
epublish
Résumé
Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in human diseases such as cancer, thus the enzymes that establish epigenetic marks, such as histone methyltransferases (HMTs), are potentially therapeutic targets. Noteworthily, HMTs form multiprotein complexes that in concert regulate gene expression. To probe epigenetic protein complexes regulation in cells, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries simultaneously on multiple histone marks inside cells. By this approach, we identified that compound 4, a published CARM1 inhibitor, inhibits both histone mark H3R2me2a, regulated also by CARM1, and H3K79me2, regulated only by DOT1L, pointing out a crosstalk between CARM1 and DOT1L. Based on this interaction, we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger inhibition of cell proliferation and increase in apoptosis, indicating that our approach identifies possible effective synergistic drug combinations.
Identifiants
pubmed: 35441144
doi: 10.1039/d1cb00095k
pii: d1cb00095k
pmc: PMC8985137
doi:
Types de publication
Journal Article
Langues
eng
Pagination
456-467Informations de copyright
This journal is © The Royal Society of Chemistry.
Déclaration de conflit d'intérêts
The authors declare that they have no conflict of interest.
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