Enhancement of O-linked N-acetylglucosamine modification promotes metastasis in patients with colorectal cancer and concurrent type 2 diabetes mellitus

Reversible post-translational modification of serine and threonine residues by O-linked N-acetylglucosamine (O-GlcNAc), termed O-GlcNAcylation has been indicated to regulate the activities of a number of different proteins. Augmented O-GlcNAcylation contributes to the etiologies of type 2 diabetes mellitus (T(2)DM) and cancer. Moreover, diabetic conditions increase the risk of colorectal cancer. However, the effect of O-GlcNAcylation in patients with colorectal cancer and concurrent T(2)DM has not been elucidated. The current study evaluated the level of O-GlcNAcylation in patients with colorectal cancer with or without T(2)DM. Notably, O-GlcNAcylation levels were significantly higher in tissues from patients with T(2)DM compared with those in patients without T(2)DM, and higher in cancer tissues compared with corresponding adjacent tissues. O-GlcNAcylation and cancer stage were more strongly correlated in cancer tissues from patients with T(2)DM compared with those from patients without T(2)DM. Additionally, distant metastasis was significantly correlated with O-GlcNAcylation in cancer tissues from patients with T(2)DM. β-catenin levels in colorectal cancer tissues were the highest in patients with advanced-stage cancer and concurrent T(2)DM. In SW480 human colon cancer cells, thiamet G (TMG) treatment and OGA silencing, which increased O-GlcNAcylation, significantly increased β-catenin and SNAIL in high-glucose, but not during normal-glucose conditions. These data suggest that O-GlcNAcylation is closely associated with distant metastasis, most likely through upregulation of the β-catenin/SNAIL signaling pathway in colorectal cancer patients with T(2)DM.