EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis,Advanced Science

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EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis
Advanced Science ( IF 14.3 ) Pub Date : 2020-09-23 , DOI: 10.1002/advs.202000681
Hyun Ho Choi _{1,

2} , Shaomin Zou _{1,

2} , Jian-Lin Wu ₃ , Huashe Wang ₄ , Liem Phan ₅ , Kai Li _{1,

2} , Peng Zhang _{1,

2} , Daici Chen _{1,

2} , Qingxin Liu _{1,

2} , Baifu Qin _{1,

2} , Thu Anh Thai Nguyen ₆ , Sai-Ching J Yeung ₇ , Lekun Fang _{1,

2,

4} , Mong-Hong Lee _{1,

2}

Affiliation

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.

中文翻译：

EGF 将信号传递给 COP1 并促进 FOXO4 降解以促进肿瘤发生

Forkhead-Box Class O 4 (FOXO4) 参与关键的生物功能，但其对 EGF-PKB/Akt 信号调节的反应尚未得到很好的表征。据报道，FOXO4 水平因 EGF 治疗而下调，同时 COP9 信号体亚基 6 (CSN6) 和 E3 泛素连接酶组成型光形态发生 1 (COP1) 水平升高。机理研究表明，CSN6 通过增强 COP1 的 E3 连接酶活性来结合并调节 FOXO4 的稳定性，并且 COP1 通过 FOXO4 上的 VP 基序直接与 FOXO4 相互作用，加速泛素介导的 FOXO4 降解。代谢组学研究表明，CSN6 表达会导致丝氨酸和甘氨酸的产生。结果表明，FOXO4 直接结合并抑制丝氨酸-甘氨酸-单碳 (SGOC) 途径基因的启动子，从而减少 SGOC 代谢。有证据表明 CSN6 可以调节 FOXO4 介导的 SGOC 基因表达。因此，这些数据表明 CSN6-FOXO4 轴和丝氨酸/甘氨酸代谢之间存在联系。此外，研究表明 CSN6-COP1-FOXO4 轴在癌症中失调，CSN6 和 FOXO4 的蛋白表达水平可以作为癌症的预后标志物。结果说明了 FOXO4 介导的丝氨酸/甘氨酸代谢通过 CSN6-COP1 轴的功能进行的途径调节。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。

更新日期：2020-10-22

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