microRNAs bidirectionally regulate FUT1 to modulate α-1,2-fucosylation and cancer-associated biology

Abstract

The -1,2-fucosyltransferase, FUT1, plays a central role in blood type determination, the establishment of the gut microbiota, and cancer progression. Using high-throughput analysis, we mapped the miRNA regulatory landscape of FUT1 and found that miRNAs bidirectionally regulate this enzyme. Validation of miRFluR assay results across multiple cell lines confirmed that both upregulatory and downregulatory miRNA interactions affect endogenous FUT1 and its enzymatic product, -1,2-fucosylation. Inhibitors of endogenous miRNA impacted both enzyme and glycan levels, underscoring the biological impact of bidirectional miRNA regulation. Upregulatory binding sites (miR-200c-5p and miR-361-3p) and the downregulatory binding site (miR-29c-5p) identified in this work both displayed non-canonical binding. Notably, miRNAs upregulating FUT1 are depleted in various cancers, aligning with observations that loss of -1,2-fucosylation is a hallmark of esophageal cancer, melanoma biogenesis, and metastasis. Furthermore, integration of our previous work with the current results indicates that the loss of miR-200c family has a strong correlation with the loss of -1,2-fucosylation during epithelial-to-mesenchymal transition. Together, these results identify miRNAs as key regulators of FUT1 and demonstrate that bidirectional miRNA control of glycosyltransferases can reshape cell-surface glycosylation with important implications for cancer biology.