EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis.
EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis.
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EGF 将信号传递给 COP1 并促进 FOXO4 降解，从而促进肿瘤发生。
DOI：
10.1002/advs.202000681
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Lee MH
中科院分区：
文献类型：
--
作者：
Choi HH;Zou S;Wu JL;Wang H;Phan L;Li K;Zhang P;Chen D;Liu Q;Qin B;Nguyen TAT;Yeung SJ;Fang L;Lee MH
Forkhead ‐ Box Class O 4（FOXO 4）参与关键的生物学功能，但其对EGF ‐ PKB/Akt信号调节的反应尚未得到很好的表征。在这里，据报道，FOXO 4水平下调响应EGF治疗，与COP9信号体亚基6（CSN 6）和E3泛素连接酶组成型光形态发生1（COP 1）水平的同时升高。机制研究表明，CSN 6通过增强COP 1的E3连接酶活性结合并调节FOXO 4的稳定性，COP 1通过FOXO 4上的VP基序直接与FOXO 4相互作用，并加速泛素介导的FOXO 4降解。代谢组学研究表明，CSN6的表达导致丝氨酸和甘氨酸的生产。研究表明，FOXO 4直接结合并抑制丝氨酸-甘氨酸-一碳（SGOC）途径基因的启动子，从而减少SGOC代谢。有证据表明，CSN 6可以调节FOXO 4介导的SGOC基因表达。因此，这些数据表明CSN 6-FOXO 4轴和ser/gly代谢的联系。此外，研究表明，CSN 6-COP 1-FOXO 4轴在癌症中失调，CSN 6和FOXO 4的蛋白表达水平可以作为癌症的预后标志物。这些结果说明了FOXO 4介导的丝氨酸/甘氨酸代谢通过CSN 6-COP 1轴功能的途径调节。对这一途径的深入了解可能会被战略性地设计用于癌症的治疗干预。Forkhead ‐ Box Class O 4（FOXO 4）水平在表皮生长因子（EGF）治疗后下调，同时COP 9信号体亚基6（CSN 6）和E3泛素连接酶组成型光形态发生1水平升高。EGF介导的FOXO4下调通过增强丝氨酸-甘氨酸-一碳基因的表达来改变癌症代谢程序。研究表明，CSN 6和FOXO 4可以作为预后标志物。
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. Forkhead‐Box Class O 4 (FOXO4) levels are downregulated in response to epidermal growth factor (EGF) treatment, with concurrent elevation of COP9 signalosome subunit 6 (CSN6) and E3 ubiquitin ligase constitutive photomorphogenic 1 levels. EGF‐mediated downregulation of FOXO4 rewires cancer metabolic programming via enhancing the expression of serine‐glycine‐one‐carbon genes. Studies demonstrate that CSN6 and FOXO4 can serve as prognostic markers.
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DOI：
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