Abstract
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.
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Acknowledgements
This work is supported by the National Natural Science Foundation of China (81874061 to TZ, 81702392 to LZ, and 81903103 to DZ).
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Conception and design: QLH, LZ, and TZ. Acquisition of data: QLH, BYZ, and GJX. Analysis and interpretation of data: QLH, BYZ, GJX, LQW, and HHW. Writing, review, and/or revision of the manuscript: QLH, BYZ, GJX, LQW, HHW, ZYL, DDY, JHR, DJZ, LZ, and TZ.
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Hua, Q., Zhang, B., Xu, G. et al. CEMIP, a novel adaptor protein of OGT, promotes colorectal cancer metastasis through glutamine metabolic reprogramming via reciprocal regulation of β-catenin. Oncogene 40, 6443–6455 (2021). https://doi.org/10.1038/s41388-021-02023-w
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DOI: https://doi.org/10.1038/s41388-021-02023-w
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