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O-GlcNAcylation-mediated degradation of FBXL2 stabilizes FOXM1 to induce cancer progression
- Source :
- Biochemical and Biophysical Research Communications. 521:632-638
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- O-GlcNAcylation is a dynamic and reversible post-translational modification of cytonuclear molecules that regulates cellular signaling. Elevated O-GlcNAcylation is a general property of cancer and plays a critical role in cancer progression. We previously showed that the expression of FOXM1, a critical oncogenic transcription factor widely overexpressed in solid tumors, was elevated in MKN45 cells, a human gastric cancer cell line, by the O-GlcNAcase inhibitor Thiamet G (TMG), which induces augmented O-GlcNAcylation. Here, we identified FBXL2 E3 ubiquitin ligase as a new target of O-GlcNAcylation. Consistent with the results in MKN45 cells, FOXM1 expression was increased, accompanied by its decreased ubiquitination and degradation by TMG in the other gastric cancer cell lines, including NUGC-3 cells. We found that FBXL2 ubiquitinated FOXM1, and the interaction with FBXL2 and ubiquitination of FOXM1 were reduced by TMG in NUGC-3 cells. Interestingly, FBXL2 was also ubiquitinated, which was promoted by TMG in the cells. Moreover, FOXM1 expression and cell proliferation were reduced in FBXL2-induced NUGC-3 cells, and the reductions were attenuated by TMG, indicating that FOXM1 was stabilized by O-GlcNAcylation-mediated degradation of FBXL2 to induce cancer progression. These data suggest that elevated O-GlcNAcylation contributes to cancer progression by suppressing FBXL2-mediated degradation of FOXM1.
- Subjects :
- 0301 basic medicine
Cell signaling
Acylation
Biophysics
Biochemistry
Acetylglucosamine
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Stomach Neoplasms
Cell Line, Tumor
medicine
Humans
Molecular Biology
Transcription factor
Cell Proliferation
biology
Protein Stability
Chemistry
Cell growth
F-Box Proteins
Forkhead Box Protein M1
Ubiquitination
Cancer
Cell Biology
medicine.disease
Cell biology
Ubiquitin ligase
030104 developmental biology
030220 oncology & carcinogenesis
Proteolysis
Disease Progression
biology.protein
FOXM1
Degradation (geology)
Subjects
Details
- ISSN :
- 0006291X
- Volume :
- 521
- Database :
- OpenAIRE
- Journal :
- Biochemical and Biophysical Research Communications
- Accession number :
- edsair.doi.dedup.....6729db92eba4d770a698dd9e7ed49f43