SIRT1 ‐mediated deacetylation of FOXO3a transcription factor supports pro‐angiogenic activity of interferon‐deficient tumor‐associated neutrophils
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Le résumé fourni par la source
Abstract Angiogenesis plays an important role during tumor growth and metastasis. We could previously show that Type I interferon (IFN)‐deficient tumor‐associated neutrophils (TANs) show strong pro‐angiogenic activity, and stimulate tumor angiogenesis and growth. However, the exact mechanism responsible for their pro‐angiogenic shift is not clear. Here, we set out to delineate the molecular mechanism and factors regulating pro‐angiogenic properties of neutrophils in the context of Type I IFN availability. We demonstrate that neutrophils from IFN‐deficient (Ifnar1−/−) mice efficiently release pro‐angiogenic factors, such as VEGF, MMP9 or BV8, and thus significantly support the vascular normalization of tumors by increasing the maturation of perivascular cells. Mechanistically, we could show here that the expression of pro‐angiogenic factors in neutrophils is controlled by the transcription factor forkhead box protein O3a (FOXO3a), which activity depends on its post‐translational modifications, such as deacetylation or phosphorylation. In TANs isolated from Ifnar1−/− mice, we observe significantly elevated SIRT1, resulting in SIRT1‐mediated deacetylation of FOXO3a, its nuclear retention and activation. Activated FOXO3a supports in turn the transcription of pro‐angiogenic genes in TANs. In the absence of SIRT1, or after its inhibition in neutrophils, elevated kinase MEK/ERK and PI3K/AKT activity is observed, leading to FOXO3a phosphorylation, cytoplasmic transfer and inactivation. In summary, we have found that FOXO3a is a key transcription factor controlling the angiogenic switch of neutrophils. Post‐translational FOXO3a modifications regulate its transcriptional activity and, as a result, the expression of pro‐angiogenic factors supporting development of vascular network in growing tumors. Therefore, targeting FOXO3a activity could provide a novel strategy of antiangiogenic targeted therapy for cancer.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- <scp>SIRT1</scp>‐mediated deacetylation of FOXO3a transcription factor supports pro‐angiogenic activity of interferon‐deficient tumor‐associated neutrophils
- Date Crossref
- 24/11/2021
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Essen University Hospital Department of Dermatology and Allergology pays non établi dans la noticeOrganisme public
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University of Duisburg-Essen pays non établi dans la noticeUniversité ou école supérieure
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West Cancer Center pays non établi dans la noticeÉtablissement de santé
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West German Heart and Vascular Center Essen pays non établi dans la noticeÉtablissement de santé
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German Cancer Research Center pays non établi dans la noticeStructure de recherche
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Deutsches Konsortium für Translationale Krebsforschung pays non établi dans la noticeStructure de recherche
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Ludwig-Maximilians-Universität München pays non établi dans la noticeUniversité ou école supérieure
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Department of Otorhinolaryngology University Hospital Essen Department of Otorhinolaryngology pays non établi dans la noticeUniversité ou école supérieure
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Medical Faculty University Duisburg‐Essen Skin Cancer Unit of the Dermatology Department pays non établi dans la noticeUniversité ou école supérieure
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Institute for Immunology University Hospital Essen pays non établi dans la noticeUniversité ou école supérieure
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German Cancer Consortium (DKTK) partner site Essen/Düsseldorf Essen Germany pays non établi dans la noticeInstitution
Department of Dermatology and Allergology — Essen University Hospital, University of Duisburg-Essen et West Cancer Center, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.