GALNT2 promotes invasiveness of colorectal cancer cells partly through AXL

GalNAc‐type O‐glycosylation and its initiating GalNAc transferases (GALNTs) play crucial roles in a wide range of cellular behaviors. Among 20 GALNT members, GALNT2 is consistently associated with poor survival of patients with colorectal cancer in public databases. However, its clinicopathological significance in colorectal cancer remains unclear. In this study, immunohistochemistry showed that GALNT2 was overexpressed in colorectal tumors compared with the adjacent nontumor tissues. GALNT2 overexpression was associated with poor survival of colorectal cancer patients. Forced expression of GALNT2 promoted migration and invasion as well as peritoneal metastasis of colorectal cancer cells. In contrast, GALNT2 knockdown with siRNAs or knockout with CRISPR/Cas9 system suppressed these malignant properties. Interestingly, we found that GALNT2 modified O‐glycans on AXL and determined AXL levels via the proteasome‐dependent pathway. In addition, the GALNT2‐promoted invasiveness was significantly reversed by AXL siRNAs. These findings suggest that GALNT2 promotes colorectal cancer invasion at least partly through AXL. TAM (TYRO3, AXL, and MERTK) receptors regulate a wide range of pathophysiological functions. Here, we show that TAM receptors are decorated with O‐glycans. GALNT2 can modify O‐glycans on AXL to increase AXL protein levels and in turn promote colon cancer cell invasiveness. This study highlights the role of GalNAc‐type O‐glycosylation in TAM receptor biology.