The GFPT2/O-GlcNAcylation/c-Myc axis promotes bladder cancer progression.

BACKGROUND

Glucose metabolic reprogramming is a hallmark of bladder cancer. However, the exact relationship between glucose metabolism and the onset and progression of bladder cancer remains poorly understood.

METHODS

We integrated a metabolic gene interaction perturbation network with machine learning algorithms to identify GFPT2 as a metabolic prognostic gene in bladder cancer. External validation was performed through survival analysis using clinical cohort data. GFPT2 expression levels was assessed by RT‒qPCR, Western blotting, and immunohistochemistry. To further explore the protumorigenic role of GFPT2, cell function experiments and animal studies were conducted. Coimmunoprecipitation and immunofluorescence techniques were used to investigate the interactions between the key downstream molecules, c-Myc and OGT, and GFPT2.

RESULTS

GFPT2 expression was higher in bladder cancer tissues than in normal tissues, and high GFPT2 expression was closely associated with poor prognosis in bladder cancer patients. GFPT2 overexpression promoted the proliferation and migration of bladder cancer cells. Mechanistic studies revealed that GFPT2 regulated the O-GlcNAcylation of c-Myc, inhibited its ubiquitination-mediated degradation, and thereby enhanced c-Myc stability, which promoted the proliferation and migration of bladder cancer cells.

CONCLUSION

This study reveals a novel mechanism involving the GFPT2/O-GlcNAcylation/c-Myc signalling axis in the malignant progression of bladder cancer. These findings provide a theoretical basis for potential new therapeutic strategies targeting bladder cancer.