BAP1 stabilizes BIRC5 to promote chemoresistance in gastric cancer

Gastric cancer is a highly aggressive malignancy associated with poor prognosis. 5-Fluorouracil (5FU) is an anticancer drug widely used to treat gastric cancer, however, the development of drug resistance during treatment remains a major clinical challenge. Therefore, understanding the molecular mechanisms underlying 5-FU resistance is essential for improving chemotherapeutic efficacy. The ubiquitin-proteasome system (UPS) is a key regulatory mechanism that controls the stability and function of intracellular proteins, with deubiquitinases (DUBs) serving as important modulators within this pathway. BRCA1-associated protein-1 (BAP1) is a representative DUB that has been implicated in tumorigenesis across various cancers; however, its role in gastric cancer and drug resistance remains poorly understood. In this study, we found that not only BAP1 but also anti-apoptotic protein BIRC5 is expressed at higher levels in 5FU-resistant gastric cancer cells compared to normal gastric cancer cells. We confirmed that BAP1 stabilizes BIRC5, a known anti-apoptotic protein, through deubiquitination. And we identified that knockdown of BAP1 reduced viability, migration, and invasion of gastric cancer cells. Furthermore, reduced BAP1 expression decreased BIRC5 protein expression, and induced apoptosis through the cleavage of PARP and Caspase-3. Notably, treatment with the selective BAP1 inhibitor iBAP-II increased the sensitivity of gastric cancer cells to 5-FU. Our findings revealed that BAP1 enhances 5-FU resistance and promotes gastric cancer progression by stabilizing BIRC5 and highlight BAP1 as a potential therapeutic target to enhance the efficacy of chemotherapy in gastric cancer.