CEMIP, a novel adaptor protein of OGT, promotes colorectal cancer metastasis through glutamine metabolic reprogramming via reciprocal regulation of β-catenin
CEMIP, a novel adaptor protein of OGT, promotes colorectal cancer metastasis through glutamine metabolic reprogramming via reciprocal regulation of β-catenin
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CEMIP是OGT的一种新型接头蛋白，通过β-连环蛋白的相互调节，通过谷氨酰胺代谢重编程促进结直肠癌转移
DOI：
10.1038/s41388-021-02023-w
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发表时间：
2021-10-04
期刊：
影响因子：
8
通讯作者：
Zhang, Tao
中科院分区：
文献类型：
--
作者：
Hua, Qingling;Zhang, Biying;Zhang, Tao
转移是结直肠癌(CRC)致死的首要原因。然而，结直肠癌转移的潜在分子机制却知之甚少。代谢重编程是癌症的内在特征，对肿瘤转移有复杂的影响。在这里，我们发现一种新的转移相关蛋白，细胞迁移诱导和透明质酸结合蛋白(CEMIP)，可以作为一种新的O-GlcNAc转移酶(OGT)的适配器蛋白，通过谷氨酰胺代谢重新编程来促进结直肠癌的转移。在机制上，CEMIP与OGT和β-连环蛋白相互作用，导致β-连环蛋白的O-GlcN酰化增加，并促进β-连环蛋白从细胞膜上的核转位。此外，细胞核内积累的β-连环蛋白增强了β-连环蛋白的转录，从而相互调节CIMIP-连环蛋白，促进谷氨酰胺酶1和谷氨酰胺转运蛋白(SLC1A5和SLC38A2)的过度表达。联合抑制CEMIP和谷氨酰胺代谢可显著降低结直肠癌的体内转移。综上所述，本研究揭示了谷氨酰胺代谢重编程在CEMIP诱导的结直肠癌转移中的重要性，表明CEMIP和谷氨酰胺代谢在预防结直肠癌转移中的巨大潜力。
Metastasis is the leading cause of colorectal cancer (CRC)-induced death. However, the underlying molecular mechanisms of CRC metastasis are poorly understood. Metabolic reprogramming is an intrinsic feature of cancer, which have complicated effects on cancer metastasis. Here, we find that a novel metastasis-related protein, cell migration-inducing and hyaluronan-binding protein (CEMIP), can act as a novel adaptor protein of O-GlcNAc transferase (OGT) to promote CRC metastasis through glutamine metabolic reprogramming. Mechanistically, CEMIP interacts with OGT and β-catenin, which leads to elevated O-GlcNAcylation of β-catenin and enhanced β-catenin nuclear translocation from cytomembrane. Furthermore, accumulated β-catenin in nucleus enhances the transcription of CEMIP to reciprocally regulate β-catenin and contributes to over-expression of glutaminase 1 and glutamine transporters (SLC1A5 and SLC38A2). Combinational inhibition of CEMIP and glutamine metabolism could dramatically attenuate the metastasis of CRC in vivo. Collectively, this study reveals the importance of glutamine metabolic reprogramming in CEMIP-induced CRC metastasis, indicating the great potential of CEMIP and glutamine metabolism for CRC metastasis prevention.