RNF25-Mediated NF-κB Activation Drives Anti-Apoptosis and Therapy Resistance in Cancer

Dysregulation of the NF-κB pathway is frequently observed in cancers, where it contributes to therapy resistance by inhibiting apoptosis. Mass spectrometry (MS)-based proteomics were employed to identify factors associated with the anti-apoptotic process. We identify RNF25, an E3 ubiquitin ligase, as a novel anti-apoptotic factor in renal cancer cells. RNF25 interacts with TRIP4 and promotes its non-degradative ubiquitination at lysine 135, preventing TRIP4 from binding to p65. This action releases p65, activating the NF-κB pathway and leading to the increased expression of anti-apoptotic genes like cIAP2 and Bcl-2.