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.
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