C2ORF68 stabilizes SIVA1 to upregulate BCL-2 and suppress apoptosis in gallbladder cancer

Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract, and its molecular drivers remain insufficiently understood. SIVA1 (apoptosis regulatory protein Siva 1) has been implicated in the regulation of cell survival, but its function in GBC has not been defined. In this study, we found that SIVA1 expression was elevated in GBC tissues and cell lines, and high SIVA1 expression was associated with poor patient prognosis. Gain- and loss-of-function experiments demonstrated that SIVA1 promoted GBC cell proliferation and migration in vitro and facilitated tumor growth in nude mice xenograft model. Mechanistically, SIVA1 was subject to ubiquitin-proteasome-mediated degradation, and we identified C2ORF68 as a binding partner that reduced SIVA1 ubiquitination and stabilized its protein level. Stabilized SIVA1 in turn increased the expression of the anti-apoptotic protein BCL-2, thereby enhancing cell survival. These findings indicate that C2ORF68-mediated stabilization of SIVA1 promotes GBC progression through BCL-2-dependent anti-apoptotic signaling, supporting SIVA1 as a potential therapeutic target.