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Genome wide CRISPR/Cas9 screen identifies the coagulation factor IX (F9) as a regulator of senescence
dc.contributor.author | Carpintero Fernández, Paula | |
dc.contributor.author | Borghesan, Michela | |
dc.contributor.author | Eleftheriadou, Olga | |
dc.contributor.author | Pan Castillo, Belén | |
dc.contributor.author | Fafian Labora, Juan | |
dc.contributor.author | Mitchell, Tom P | |
dc.contributor.author | García Yuste, Alejandro | |
dc.contributor.author | Ogrunc, Muge | |
dc.contributor.author | Nightingale, Thomas D. | |
dc.contributor.author | Mayán Santos, María Dolores | |
dc.contributor.author | O'Loghlen, Ana | |
dc.date.accessioned | 2022-11-24T12:29:52Z | |
dc.date.available | 2022-11-24T12:29:52Z | |
dc.date.issued | 2022-02-19 | |
dc.identifier.other | https://pubmed.ncbi.nlm.nih.gov/35184131/ | es |
dc.identifier.uri | http://hdl.handle.net/20.500.11940/17064 | |
dc.description.abstract | 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. | es |
dc.description.sponsorship | BBSRC (BB/ P000223/1) | es |
dc.description.sponsorship | MRC (MR/K501372/1) | es |
dc.description.sponsorship | The Royal Society (RG170399) | es |
dc.description.sponsorship | Barts Charity (MGU0497 and G-002158) | es |
dc.description.sponsorship | PI19/00145 | es |
dc.description.sponsorship | IN607B2020/12 | es |
dc.description.sponsorship | H2020, Future and Emerging Technologies (grant 858014 “PANACHE”) | es |
dc.description.sponsorship | Barts Charity/G-002158 | es |
dc.description.sponsorship | Xunta de Galicia | es |
dc.language.iso | eng | es |
dc.rights | Attribution 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Breast Neoplasms | * |
dc.subject.mesh | Cell Line, Tumor | * |
dc.subject.mesh | Factor IX | * |
dc.title | Genome wide CRISPR/Cas9 screen identifies the coagulation factor IX (F9) as a regulator of senescence | es |
dc.type | Artigo | es |
dc.rights.holder | Autores | es |
dc.identifier.doi | 10.1038/s41419-022-04569-3. | |
dc.identifier.pmid | 35184131 | |
dc.issue.number | 2 | es |
dc.journal.title | Cell Death and Disease | es |
dc.organization | Servizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::Instituto de Investigación Biomédica da Coruña (INIBIC) | es |
dc.organization | Servizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::EOXI de A Coruña - Complexo Hospitalario Universitario de A Coruña | es |
dc.page.initial | 163 | es |
dc.relation.projectID | BBSRC/BB/P000223/1 | es |
dc.relation.projectID | MRC/MR/K501372/1 | es |
dc.relation.projectID | The Royal Society/RG170399 | es |
dc.relation.projectID | Barts Charity/MGU0497 | es |
dc.relation.projectID | Xunta de Galicia/ED481B 2017/117 | es |
dc.relation.projectID | PI19/00145 | es |
dc.relation.projectID | IN607B2020/12 | es |
dc.relation.projectID | Barts Charity/MGU0534 | es |
dc.relation.projectID | Xunta de Galicia/GAIN/IN606C 2021/006 | es |
dc.relation.publisherversion | https://www.nature.com/articles/s41419-022-04569-3 | es |
dc.rights.accessRights | openAccess | es |
dc.subject.decs | neoplasias de la mama | * |
dc.subject.decs | línea celular tumoral | * |
dc.subject.decs | factor IX | * |
dc.subject.keyword | INIBIC | es |
dc.subject.keyword | CHUAC | es |
dc.typefides | Artigo Científico (inclue Orixinal, Orixinal breve, Revisión Sistemática e Meta-análisis) | es |
dc.typesophos | Artículo Original | es |
dc.volume.number | 13 | es |
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