SIRT1-mediated deacetylation of FOXO3a transcription factor supports pro-angiogenic activity of interferon-deficient tumor-associated neutrophils.

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.

• Authors: Sharareh Bordbari, Britta Mörchen, Ekaterina Pylaeva, Elena Siakaeva, Ilona Spyra, Maksim Domnich, Freya Droege, Oliver Kanaan, Karl Sebastian Lang, Dirk Schadendorf, Stephan Lang, Iris Helfrich, Jadwiga Jablonska
• Journal: International journal of cancer (Int J Cancer) Vol. 150 Issue 7 Pg. 1198-1211 (04 01 2022) ISSN: 1097-0215 [Electronic] United States
• PMID: 34751438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Interferon Type I
• SIRT1 protein, human
• Sirtuin 1

Topics

• Acetylation
• Animals
• Cell Line, Tumor
• Forkhead Box Protein O3 (metabolism)
• Humans
• Interferon Type I (physiology)
• Mice
• Mice, Inbred C57BL
• Neoplasms (blood supply)
• Neovascularization, Pathologic (etiology)
• Neutrophils (physiology)
• Protein Processing, Post-Translational
• Sirtuin 1 (physiology)