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

August-2020 Volume 20 Issue 2

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

August-2020 Volume 20 Issue 2

Full Size Image

Article Open Access

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
View Affiliations / Copyright

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

Copyright: © Naka et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 1171-1178
|
Published online on: May 22, 2020

https://doi.org/10.3892/ol.2020.11665
Expand metrics +

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.

View Figures

View References

1	Hart GW, Housley MP and Slawson C: Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins. Nature. 446:1017–1022. 2007. View Article : Google Scholar : PubMed/NCBI
2	Iyer SP and Hart GW: Dynamic nuclear and cytoplasmic glycosylation: Enzymes of O-GlcNAc cycling. Biochemistry. 42:2493–2499. 2003. View Article : Google Scholar : PubMed/NCBI
3	Zachara NE, O'Donnell N, Cheung WD, Mercer JJ, Marth JD and Hart GW: Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. J Biol Chem. 279:30133–30142. 2004. View Article : Google Scholar : PubMed/NCBI
4	Hart GW, Slawson C, Ramirez-Correa G and Lagerlof O: Cross talk between O-GlcNAcylation and phosphorylation: Roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 80:825–858. 2011. View Article : Google Scholar : PubMed/NCBI
5	Griffith LS and Schmitz B: O-linked N-acetylglucosamine levels in cerebellar neurons respond reciprocally to pertubations of phosphorylation. Eur J Biochem. 262:824–831. 1999. View Article : Google Scholar : PubMed/NCBI
6	Vosseller K, Wells L, Lane MD and Hart GW: Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. Proc Natl Acad Sci USA. 99:5313–5318. 2002. View Article : Google Scholar : PubMed/NCBI
7	McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC and Hanover JA: Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. Proc Natl Acad Sci USA. 99:10695–10699. 2002. View Article : Google Scholar : PubMed/NCBI
8	Lefebvre T, Ferreira S, Dupont-Wallois L, Bussière T, Dupire MJ, Delacourte A, Michalski JC and Caillet-Boudin ML: Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins--a role in nuclear localization. Biochim Biophys Acta. 1619:167–176. 2003. View Article : Google Scholar : PubMed/NCBI
9	Yokoe S, Asahi M, Takeda T, Otsu K, Taniguchi N, Miyoshi E and Suzuki K: Inhibition of phospholamban phosphorylation by O-GlcNAcylation: Implications for diabetic cardiomyopathy. Glycobiology. 20:1217–1226. 2010. View Article : Google Scholar : PubMed/NCBI
10	Slawson C, Pidala J and Potter R: Increased N-acetyl-beta-glucosaminidase activity in primary breast carcinomas corresponds to a decrease in N-acetylglucosamine containing proteins. Biochim Biophys Acta. 1537:147–157. 2001. View Article : Google Scholar : PubMed/NCBI
11	Moriwaki K and Asahi M: Augmented TME O-GlcNAcylation Promotes Tumor Proliferation through the Inhibition of p38 MAPK. Mol Cancer Res. 15:1287–1298. 2017. View Article : Google Scholar : PubMed/NCBI
12	McClain DA and Crook ED: Hexosamines and insulin resistance. Diabetes. 45:1003–1009. 1996. View Article : Google Scholar : PubMed/NCBI
13	Brownlee M: The pathobiology of diabetic complications: A unifying mechanism. Diabetes. 54:1615–1625. 2005. View Article : Google Scholar : PubMed/NCBI
14	Buse MG, Robinson KA, Marshall BA, Hresko RC and Mueckler MM: Enhanced O-GlcNAc protein modification is associated with insulin resistance in GLUT1-overexpressing muscles. Am J Physiol Endocrinol Metab. 283:E241–E250. 2002. View Article : Google Scholar : PubMed/NCBI
15	Mi W, Gu Y, Han C, Liu H, Fan Q, Zhang X, Cong Q and Yu W: O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy. Biochim Biophys Acta. 1812:514–519. 2011. View Article : Google Scholar : PubMed/NCBI
16	Deng L, Gui Z, Zhao L, Wang J and Shen L: Diabetes mellitus and the incidence of colorectal cancer: An updated systematic review and meta-analysis. Dig Dis Sci. 57:1576–1585. 2012. View Article : Google Scholar : PubMed/NCBI
17	Calle EE and Kaaks R: Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 4:579–591. 2004. View Article : Google Scholar : PubMed/NCBI
18	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
19	Xue C, Plieth D, Venkov C, Xu C and Neilson EG: The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res. 63:3386–3394. 2003.PubMed/NCBI
20	Greenburg G and Hay ED: Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol. 95:333–339. 1982. View Article : Google Scholar : PubMed/NCBI
21	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
22	Moon RT, Kohn AD, De Ferrari GV and Kaykas A: WNT and beta-catenin signalling: Diseases and therapies. Nat Rev Genet. 5:691–701. 2004. View Article : Google Scholar : PubMed/NCBI
23	Polakis P: The many ways of Wnt in cancer. Curr Opin Genet Dev. 17:45–51. 2007. View Article : Google Scholar : PubMed/NCBI
24	Prasad CP, Mirza S, Sharma G, Prashad R, DattaGupta S, Rath G and Ralhan R: Epigenetic alterations of CDH1 and APC genes: Relationship with activation of Wnt/beta-catenin pathway in invasive ductal carcinoma of breast. Life Sci. 83:318–325. 2008. View Article : Google Scholar : PubMed/NCBI
25	Iwai S, Yonekawa A, Harada C, Hamada M, Katagiri W, Nakazawa M and Yura Y: Involvement of the Wnt-β-catenin pathway in invasion and migration of oral squamous carcinoma cells. Int J Oncol. 37:1095–1103. 2010. View Article : Google Scholar : PubMed/NCBI
26	Gonzalez DM and Medici D: Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 7:re82014. View Article : Google Scholar : PubMed/NCBI
27	Vu T and Datta PK: Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis. Cancers (Basel). 9:171–192. 2017. View Article : Google Scholar
28	Jiang M, Xu B, Li X, Shang Y, Chu Y, Wang W, Chen D, Wu N, Hu S, Zhang S, et al: O-GlcNAcylation promotes colorectal cancer metastasis via the miR-101-O-GlcNAc/EZH2 regulatory feedback circuit. Oncogene. 38:301–316. 2019. View Article : Google Scholar : PubMed/NCBI
29	Ling L, Chen L, Zhang C, Gui S, Zhao H and Li Z: High glucose induces podocyte epithelial-to-mesenchymal transition by demethylation-mediated enhancement of MMP9 expression. Mol Med Rep. 17:5642–5651. 2018.PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Related Articles