FUT2 promotes colorectal cancer metastasis by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1

Abstract

Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide because of high rate of metastasis, approximately 20% of CRC patients have metastases at initial diagnosis. Metabolism reprogramming, as a universal feature for cancer cells, is considered to be associated with metastasis. We have previously demonstrated that fucosyltransferase 2 (FUT2) functions as a potent oncogene in CRC, and promotes the development and malignancy of CRC cells, however, the underlying mechanism remains unclear. Here, bioinformatic analysis indicated that FUT2 was related to malignant phenotype and fatty acid metabolism in CRC. FUT2 knockdown decreased glucose uptake and de novo fatty acid synthesis, which in turn inhibited the proliferation and metastasis of CRC cells. Mechanistically, FUT2 promotes YAP1 nuclear translocation and concurrently stabilizing mSREBP-1 by fucosylation, thus promoting de novo fatty acid synthesis in CRC cells. Furthermore, a prognostic model, constructed based on YAP1, SREBP-1, FUT2, and FASN, has high accuracy in the OS of CRC patients. In summary, this study demonstrates that FUT2 reprograms fatty acid metabolism of CRC cells via Hippo signaling pathway and SREBP-1. The findings imply that FUT2 might be a potential target for the development of therapeutic strategies against CRC.