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

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

doi:10.3892/ol.2020.11665

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

Authors:
- Yutaka Naka
- Toshihiko Okada
- Takatoshi Nakagawa
- Eiko Kobayashi
- Yuka Kawasaki
- Yasuyoshi Tanaka
- Hideki Tawa
- Yuki Hirata
- Ken Kawakami
- Kazuki Kakimoto
- Takuya Inoue
- Toshihisa Takeuchi
- Shinya Fukunishi
- Yoshinobu Hirose
- Kazuhisa Uchiyama
- Michio Asahi
- Kazuhide Higuchi
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Affiliations: Second Department of Internal Medicine, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569‑8686, Japan, Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569‑8686, Japan, Department of Pathology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569‑8686, Japan, Department of General and Gastroenterological Surgery, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569‑8686, Japan
Published online on: May 22, 2020 https://doi.org/10.3892/ol.2020.11665
Pages: 1171-1178
Copyright: © Naka et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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 (T2DM) and cancer. Moreover, diabetic conditions increase the risk of colorectal cancer. However, the effect of O‑GlcNAcylation in patients with colorectal cancer and concurrent T2DM has not been elucidated. The current study evaluated the level of O‑GlcNAcylation in patients with colorectal cancer with or without T2DM. Notably, O‑GlcNAcylation levels were significantly higher in tissues from patients with T2DM compared with those in patients without T2DM, 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 T2DM compared with those from patients without T2DM. Additionally, distant metastasis was significantly correlated with O‑GlcNAcylation in cancer tissues from patients with T2DM. β‑catenin levels in colorectal cancer tissues were the highest in patients with advanced‑stage cancer and concurrent T2DM. 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 T2DM.

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