MZT1 protects gastric cancer against glucose starvation through targeting NEDD1

A fasting mimic diet (FMD) has been proven to be a potential therapeutic regimen for gastric cancer (GC) patients. However, the intolerance of energy restriction and limited efficacies hinder wide application of FMD. To identify critical targets mediating resistance against glucose starvation and explore novel approaches to GC therapy, proteomics profiling was performed to depict the landscape of protein expression changes in cells under glucose deprivation. MZT1 was found to be greatly upregulated. We next investigated potential clinical value and regulatory functions of MZT1. Compared to adjacent normal tissues, MZT1 was upregulated in GC specimens and associated with unfavorable patient prognosis. Both in vitro and in vivo experiments indicated that downregulation of the MZT1 level inhibited GC proliferation, migration, invasion, glycolysis and sensitized cells to glucose starvation. Mechanistically, MZT1 functioned as an oncogenic factor by inhibiting NEDD1 ubiquitination and increasing its expression. In conclusion, during glucose starvation, MZT1 is upregulated in GC cells, which promotes resistance by directly suppression of NEDD1 ubiquitination. Our findings unveil the novel mechanisms by which MZT1 can promote GC malignancy. The potential clinical value of MZT1 as GC biomarkers has been first revealed. Suppression of MZT1 may become a promising approach to improve FMD efficacy, which require further validation by future investigations.