Inhibition of BAP1 Sensitizes Gastric Cancer Cells to 5-Fluorouracil by Promoting BIRC5 Degradation

Background/Objectives: Gastric cancer is an aggressive malignancy with poor prognosis, and acquired resistance to 5-fluorouracil (5-FU) remains a major therapeutic challenge. BRCA1-associated protein-1 (BAP1), a deubiquitinating enzyme, has been implicated in tumorigenesis; however, its role in gastric cancer and 5-FU resistance remains unclear. This study investigated the functional and molecular roles of BAP1 in gastric cancer progression and chemoresistance. Methods: BAP1 expression and its association with patient prognosis were evaluated in gastric cancer tissues. The effects of BAP1 depletion on cancer cell proliferation, migration, invasion, and apoptosis were examined. The interaction between BAP1 and BIRC5 (Survivin) and the effects of BAP1-mediated deubiquitination on BIRC5 stability were investigated. The therapeutic effect of the BAP1 inhibitor iBAP-II was further assessed in 5-FU resistant gastric cancer cells. Results: BAP1 was significantly upregulated in gastric cancer tissues and associated with poor prognosis. BAP1 knockdown suppressed proliferation, migration, and invasion. Further analysis revealed that BAP1 interacted with and stabilized BIRC5 through deubiquitination, thereby suppressing apoptosis. BAP1 and BIRC5 were markedly upregulated in 5-FU resistant cells, whereas iBAP-II treatment enhanced 5-FU sensitivity and increased caspase-3 and PARP cleavage. Conclusions: BAP1 promotes gastric cancer progression and 5-FU resistance by stabilizing BIRC5. Targeting the BAP1–BIRC5 axis may represent a promising strategy for overcoming 5-FU resistance and improving therapeutic efficacy in gastric cancer.