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

• Published in: Oncology letters 2020-08, Vol.20 (2), p.1171-1178
• Main Authors: Naka, Yutaka, Okada, Toshihiko, Nakagawa, Takatoshi, Kobayashi, Eiko, Kawasaki, Yuka, Tanaka, Yasuyoshi, Tawa, Hideki, Hirata, Yuki, Kawakami, Ken, Kakimoto, Kazuki, Inoue, Takuya, Takeuchi, Toshihisa, Fukunishi, Shinya, Hirose, Yoshinobu, Uchiyama, Kazuhisa, Asahi, Michio, Higuchi, Kazuhide
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Antibodies; Biosynthesis; Cancer metastasis; Cancer patients; Cancer research; Colorectal cancer; Comparative analysis; Development and progression; Diabetes; Glucose; Health aspects; Insulin resistance; Laboratories; Lung cancer; Lymphatic system; Metastasis; Oncology; Penicillin; Phosphorylation; Post-translational modifications; Proteins; Scientific equipment industry; Type 2 diabetes
• ISSN: 1792-1074; 1792-1082
• DOI: 10.3892/ol.2020.11665

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.sub.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.sub.2]DM has not been elucidated. The current study evaluated the level of O-GlcNAcylation in patients with colorectal cancer with or without [T.sub.2]DM. Notably, O-GlcNAcylation levels were significantly higher in tissues from patients with [T.sub.2]DM compared with those in patients without [T.sub.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.sub.2]DM compared with those from patients without [T.sub.2]DM. Additionally, distant metastasis was significantly correlated with O-GlcNAcylation in cancer tissues from patients with [T.sub.2]DM. p-catenin levels in colorectal cancer tissues were the highest in patients with advanced-stage cancer and concurrent [T.sub.2]DM. In SW480 human colon cancer cells, thiamet G (TMG) treatment and OGA silencing, which increased O-GlcNAcylation, significantly increased p-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 p-catenin/SNAIL signaling pathway in colorectal cancer patients with [T.sub.2]DM.