RAB3A-mediated BAG6 translocation promotes non-small cell lung cancer tumorigenesis and progression.

PURPOSE: RAB3A, a member of the RAS oncogene family, plays a central role in regulated exocytosis and secretion. However, its function, molecular mechanism, and clinical significance in non-small cell lung cancer(NSCLC) remain largely undetermined. METHODS: We analyzed the expression of RAB3A and its correlation with overall survival using multiple databases and immunohistochemistry staining. The oncogenic role of RAB3A in NSCLC was investigated through various cellular assays, including cell viability and colony formation assays. Protein mass spectrometry experiment, immunoprecipitation, immunofluorescence, subcellular fractionation, mitochondria isolation, cycloheximide assays, and lung cancer xenograft mouse models were performed to clarify the molecular mechanism of RAB3A in NSCLC progression. RESULTS: The expression of RAB3A was upregulated in NSCLC patients and high level of RAB3A correlated with a poor overall survival. RAB3A depletion inhibited the cell proliferation. Mechanistically, RAB3A knockdown enhanced the nuclear translocation of BAG6-EP300, leading to the acetylation of p53 and Rb. This acetylation strengthened the p53/Rb signaling pathway, thereby suppressing NSCLC progression. Additionally, RAB3A facilitated the transportation of BAG6 to the mitochondria, promoting mitophagy and increasing resistance to cisplatin in NSCLC cells. CONCLUSION: Our findings elucidate the role and underlying mechanisms of RAB3A in NSCLC progression. Thus, RAB3A emerges as a potential prognosis prediction biomarker and therapeutic target for NSCLC patients. CLINICAL TRIAL NUMBER: Not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13402-025-01123-z.