Abstract
Forkhead-Box Class O 4 (FOXO4) is involved in critical biological functions, but its response to EGF-PKB/Akt signal regulation is not well characterized. Here, it is reported that FOXO4 levels are downregulated in response to EGF treatment, with concurrent elevation of COP9 Signalosome subunit 6 (CSN6) and E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) levels. Mechanistic studies show that CSN6 binds and regulates FOXO4 stability through enhancing the E3 ligase activity of COP1, and that COP1 directly interacts with FOXO4 through a VP motif on FOXO4 and accelerates the ubiquitin-mediated degradation of FOXO4. Metabolomic studies demonstrate that CSN6 expression leads to serine and glycine production. It is shown that FOXO4 directly binds and suppresses the promoters of serine-glycine-one-carbon (SGOC) pathway genes, thereby diminishing SGOC metabolism. Evidence shows that CSN6 can regulate FOXO4-mediated SGOC gene expression. Thus, these data suggest a link of CSN6-FOXO4 axis and ser/gly metabolism. Further, it is shown that CSN6-COP1-FOXO4 axis is deregulated in cancer and that the protein expression levels of CSN6 and FOXO4 can serve as prognostic markers for cancers. The results illustrate a pathway regulation of FOXO4-mediated serine/glycine metabolism through the function of CSN6-COP1 axis. Insights into this pathway may be strategically designed for therapeutic intervention in cancers.
Original language | English (US) |
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Article number | 2000681 |
Journal | Advanced Science |
Volume | 7 |
Issue number | 20 |
DOIs | |
State | Published - Oct 1 2020 |
Keywords
- COP1
- COP9
- CSN
- FOXO4
- SGOC
ASJC Scopus subject areas
- Medicine (miscellaneous)
- General Chemical Engineering
- General Materials Science
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- General Engineering
- General Physics and Astronomy