FUT2-Mediated Fucosylation of OLFM4 Promotes Colon Cancer Cell Differentiation

Fucosyltransferase 2 (FUT2) deficiency exacerbates inflammation, a known risk factor for colon cancer. However, the precise role and underlying mechanism of FUT2 in regulating colon cancer cell differentiation remain unclear. Although olfactomedin-4 (OLFM4) has been known to have a tumor-suppressive effect, its functional interaction with FUT2 in colon cancer remains unexplored.

FUT2 expression levels were assessed using TCGA and cBioPortal databases and in different colon cancer cell lines. ALP assays were performed to evaluate the effect of FUT2 on cancer cell differentiation. Transwell invasion assays, scratch assays, and tumor sphere formation assays were used to investigate the functional effects of FUT2 on colon cancer cells. N-glycosylation proteomics and UEA-I chromatography were used to identify the regulatory effect of FUT2 on OLFM4 fucosylation.

FUT2 expression was associated with the differentiation degree of colon cancer cell lines. Based on their endogenous FUT2 expression, we overexpressed FUT2 in SW480 cells (low baseline) and knocked it down in HT29 cells (high baseline). Overexpressing FUT2 promoted the differentiation of SW480 cells and inhibited their migration, invasion, EMT, and stemness. Conversely, knockdown of FUT2 in HT29 cells reduced its degree of differentiation and increased its malignancy. N-glycosylation proteomics analysis and UEA-I chromatography indicated OLFM4 as a downstream target of FUT2. FUT2-mediated fucosylation of OLFM4 is positively correlated with the degree of cancer cell differentiation. Knockdown of OLFM4 attenuated differentiation in FUT2-overexpressing SW480 cells, while overexpression of OLFM4 produced opposite effects.

FUT2 promotes colon cancer cell differentiation by mediating OLFM4 fucosylation, suggesting that FUT2 may serve as a therapeutic target for colon cancer.