Genome wide CRISPR/Cas9 screen identifies the coagulation factor IX (F9) as a regulator of senescence.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
19 02 2022
19 02 2022
Historique:
received:
08
04
2021
accepted:
17
01
2022
revised:
22
12
2021
entrez:
20
2
2022
pubmed:
21
2
2022
medline:
9
4
2022
Statut:
epublish
Résumé
During this last decade, the development of prosenescence therapies has become an attractive strategy as cellular senescence acts as a barrier against tumour progression. In this context, CDK4/6 inhibitors induce senescence and reduce tumour growth in breast cancer patients. However, even though cancer cells are arrested after CDK4/6 inhibitor treatment, genes regulating senescence in this context are still unknown limiting their antitumour activity. Here, using a functional genome-wide CRISPR/Cas9 genetic screen we found several genes that participate in the proliferation arrest induced by CDK4/6 inhibitors. We find that downregulation of the coagulation factor IX (F9) using sgRNA and shRNA prevents the cell cycle arrest and senescent-like phenotype induced in MCF7 breast tumour cells upon Palbociclib treatment. These results were confirmed using another breast cancer cell line, T47D, and with an alternative CDK4/6 inhibitor, Abemaciclib, and further tested in a panel of 22 cancer cells. While F9 knockout prevents the induction of senescence, treatment with a recombinant F9 protein was sufficient to induce a cell cycle arrest and senescence-like state in MCF7 tumour cells. Besides, endogenous F9 is upregulated in different human primary cells cultures undergoing senescence. Importantly, bioinformatics analysis of cancer datasets suggest a role for F9 in human tumours. Altogether, these data collectively propose key genes involved in CDK4/6 inhibitor response that will be useful to design new therapeutic strategies in personalised medicine in order to increase their efficiency, stratify patients and avoid drug resistance.
Identifiants
pubmed: 35184131
doi: 10.1038/s41419-022-04569-3
pii: 10.1038/s41419-022-04569-3
pmc: PMC8858321
doi:
Substances chimiques
Factor IX
9001-28-9
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
163Subventions
Organisme : RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
ID : BB/P000223/1
Organisme : Office of the Royal Society
ID : RG170399
Organisme : Medical Research Council
ID : MR/K501372/1
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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