DLGAP5 enhances chemotherapy resistance in pancreatic ductal adenocarcinoma by regulating glycolysis through MYC.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is widely recognized as the most lethal malignancy of the digestive system. Its poor prognosis is largely attributed to a high degree of resistance to gemcitabine (GEM), highlighting the critical need to elucidate the underlying mechanisms of GEM resistance for effective therapeutic intervention. DLGAP5, a cell cycle-associated protein, has been implicated in PDAC progression; however, its potential role in regulating glycolysis and GEM resistance remains unclear. METHODS: The expression level and prognostic significance of DLGAP5 in PDAC were evaluated using bioinformatics analysis and Western blotting. In vitro tumorigenic assays were conducted to assess the impact of DLGAP5 on cellular proliferation. Furthermore, the interactions between DLGAP5 and MYC or USP11 were investigated through biochemical assays, protein-protein interaction studies, and gene expression analyses. RESULTS: Our findings demonstrate that DLGAP5 promotes glycolytic metabolism and confers resistance to GEM in PDAC. High DLGAP5 expression correlates with adverse clinical outcomes in PDAC patients. Mechanistically, DLGAP5 facilitates the deubiquitination of MYC via interaction with USP11, thereby enhancing MYC protein stability and promoting both GEM resistance and glycolytic activity. CONCLUSION: DLGAP5 modulates MYC protein stability through the USP11-mediated deubiquitination pathway. Targeting the DLGAP5-USP11-MYC signaling axis may represent a promising therapeutic strategy to overcome GEM resistance in PDAC.