FUT2-mediated OLFM4 fucosylation drives colon cancer cell differentiation and suppresses malignancy

Colon cancer remains a significant global health challenge, with inflammation recognized as a key risk factor. While Fucosyltransferase 2 (FUT2) deficiency is linked to exacerbated inflammation, its precise role in regulating colon cancer cell differentiation has been unclear. Olfactomedin-4 (OLFM4) is known for its tumor-suppressive effects, yet its functional interplay with FUT2 in this context was previously unexplored. Understanding this interaction could reveal novel therapeutic avenues to restore differentiation, a critical process often lost in aggressive cancers.

Researchers investigated FUT2's role in colon cancer using SW480 and HT29 cell lines. They assessed FUT2 expression via TCGA and cBioPortal databases. To study function, FUT2 was overexpressed in SW480 cells (low baseline) and knocked down in HT29 cells (high baseline). Cell differentiation was evaluated using ALP assays. Malignant behaviors like migration, invasion, and stemness were assessed through Transwell invasion assays, scratch assays, and tumor sphere formation assays. N-glycosylation proteomics and UEA-I chromatography identified OLFM4 as a downstream target, with subsequent OLFM4 knockdown and overexpression experiments confirming its role.

FUT2 expression correlated with the differentiation status of colon cancer cell lines. Overexpression of FUT2 in SW480 cells significantly promoted differentiation and inhibited key malignant traits: migration, invasion, EMT, and stemness. Conversely, knocking down FUT2 in HT29 cells reduced differentiation and enhanced malignancy. > N-glycosylation proteomics and UEA-I chromatography identified OLFM4 as a direct downstream target, revealing that FUT2-mediated fucosylation of OLFM4 is positively correlated with the degree of cancer cell differentiation. Further experiments confirmed OLFM4's critical role: OLFM4 knockdown attenuated differentiation in FUT2-overexpressing SW480 cells, while OLFM4 overexpression produced the opposite effect, restoring differentiation. These findings establish a direct regulatory axis where FUT2 drives differentiation by modifying OLFM4.