ILF3 is a substrate of SPOP for regulating serine biosynthesis in colorectal cancer
ILF3 is a substrate of SPOP for regulating serine biosynthesis in colorectal cancer
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ILF3 是 SPOP 的底物，用于调节结直肠癌中的丝氨酸生物合成。
DOI：
10.1038/s41422-019-0257-1
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发表时间：
2020-02-01
期刊：
影响因子：
44.1
通讯作者：
Lee, Mong-Hong
中科院分区：
文献类型：
--
作者：
Li, Kai;Wu, Jian-lin;Lee, Mong-Hong
丝氨酸-甘氨酸-一碳（SGOC）途径在多种合成代谢过程中是关键的。SGOC基因的表达水平在致瘤条件下失调，表明癌基因参与了SGOC生物合成途径的失调。然而，根本的机制仍然难以捉摸。在此，我们发现白细胞介素增强子结合因子3（ILF 3）在原发性结直肠癌患者标本中过表达，并与不良预后相关。ILF 3通过直接调节SGOC基因的mRNA稳定性，从而增加SGOC基因表达并促进肿瘤生长，在调节SGOC通路中至关重要。机制研究表明，EGF-MEK-ERK途径介导的ILF 3磷酸化，这阻碍了E3连接酶斑点型POZ蛋白（SPOP）介导的多聚泛素化和降解ILF 3。值得注意的是，SGOC抑制剂和抗EGFR单克隆抗体西妥昔单抗的组合可以阻碍维持高ERK-ILF 3水平的患者来源的异种移植物的生长。总之，通过EGF-ERK信号转导的ILF 3的失调在系统性丝氨酸代谢重编程中起重要作用，并赋予CRC发展的偏好。我们的研究结果表明，SGOC抑制剂的临床评价是必要的CRC患者与ILF 3过表达。
The Serine-Glycine-One-Carbon (SGOC) pathway is pivotal in multiple anabolic processes. Expression levels of SGOC genes are deregulated under tumorigenic conditions, suggesting participation of oncogenes in deregulating the SGOC biosynthetic pathway. However, the underlying mechanism remains elusive. Here, we identified that Interleukin enhancer-binding factor 3 (ILF3) is overexpressed in primary CRC patient specimens and correlates with poor prognosis. ILF3 is critical in regulating the SGOC pathway by directly regulating the mRNA stability of SGOC genes, thereby increasing SGOC genes expression and facilitating tumor growth. Mechanistic studies showed that the EGF-MEK-ERK pathway mediates ILF3 phosphorylation, which hinders E3 ligase speckle-type POZ protein (SPOP)-mediated poly-ubiquitination and degradation of ILF3. Significantly, combination of SGOC inhibitor and the anti-EGFR monoclonal antibody cetuximab can hinder the growth of patient-derived xenografts that sustain high ERK-ILF3 levels. Taken together, deregulation of ILF3 via the EGF-ERK signaling plays an important role in systemic serine metabolic reprogramming and confers a predilection toward CRC development. Our findings indicate that clinical evaluation of SGOC inhibitor is warranted for CRC patients with ILF3 overexpression.