CEMIP, a novel adaptor protein of OGT, promotes colorectal cancer metastasis through glutamine metabolic reprogramming via reciprocal regulation of β-catenin

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 beta-catenin, which leads to elevated O-GlcNAcylation of beta-catenin and enhanced beta-catenin nuclear translocation from cytomembrane. Furthermore, accumulated beta-catenin in nucleus enhances the transcription of CEMIP to reciprocally regulate beta-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.

Automated summary

Metastasis in colorectal cancer is driven by metabolic reprogramming, with the novel protein CEMIP acting as an adaptor for OGT to promote glutamine metabolism and metastasis. CEMIP interacts with OGT and beta-catenin to enhance beta-catenin nuclear translocation and increase the expression of glutaminase 1. Combining inhibition of CEMIP and glutamine metabolism can effectively reduce CRC metastasis in vivo.