Loss of ST8SIA6 is associated with enhanced MUC16-Integrin β4 signaling and aggressive phenotypes in colorectal cancer.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, underscoring the need to better understand tumor-intrinsic mechanisms underlying aggressive disease progression. Aberrant glycosylation is increasingly recognized as a key regulator of cancer cell behavior; however, the functional contribution of α2,8-sialylation to CRC remains poorly defined. Here, we investigated the role of the α2,8-sialyltransferase (ST8SIA6) in CRC progression and its impact on mucin-mediated signaling. Analysis of human CRC tissue arrays showed that ST8SIA6 expression was reduced in higher-stage tumors. ST8SIA6 silencing enhanced migration and invasion and was associated with EMT-like molecular changes. Using Siglec-7-based lectin enrichment and proteomic analysis, we identified MUC16 as a prominent Siglec-7-reactive glycoprotein associated with ST8SIA6. Loss of ST8SIA6 reduced Siglec-7 reactivity of MUC16 and increased its cell-surface localization. Increased membrane-associated MUC16 was accompanied by enhanced association with integrin β4 and increased Src and FAK phosphorylation. Blockade of integrin β4 attenuated Src/FAK activation and suppressed CRC cell migration, supporting a functional role for this axis. In vivo, ST8SIA6-deficient CRC cells exhibited increased lung tumor colonization following tail-vein injection in xenograft models, accompanied by elevated membrane MUC16 and increased MUC16-integrin β4 colocalization. Consistent with these findings, human CRC specimens from advanced stages exhibited increased MUC16 expression and integrin β4 colocalization compared with early-stage tumors. Together, these findings support a model in which loss of ST8SIA6 enhances MUC16-integrin β4 signaling and contributes to aggressive CRC phenotypes through increased MUC16 membrane localization and integrin β4-dependent signaling. These findings identify a previously unrecognized glycosylation-associated signaling axis that warrants further investigation as a biomarker and potential therapeutic target in colorectal cancer.