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

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lei Li

PROVIDER: PXD061521 | iProX | Wed Mar 05 00:00:00 GMT 2025

REPOSITORIES: iProX

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BAY11-7082 Targets RNF25 to Reverse TRIP4 Ubiquitination-dependent NF-κB Activation and Apoptosis Resistance in Renal Cell Carcinoma.

Li Lei L Wang Zixi Z Ma Bohan B Ye Qi Q Lei Yuzeshi Y Lu Mingming M Ye Leihong L Kang Jialu J Huang Wenyue W Xu Shan S Wang Ke K Chen Yule Y Liu Jing J Gao Yang Y Wang Chenji C Ma Jian J Li Lei L

International journal of biological sciences 20250704 10

NF-κB pathway dysregulation, a common driver of therapy resistance in cancer, promotes survival by suppressing apoptosis. While the anti-apoptotic role of NF-κB is recognized, the molecular mechanisms underlying this process remain poorly defined. Here, we identify the E3 ubiquitin ligase RNF25 as a key mediator of NF-κB-dependent apoptosis resistance in renal cell carcinoma cells, enabling evasion of multiple targeted therapies. Mechanistically, RNF25 binds TRIP4 and catalyzes its non-degradati ...[more]

PMID: 40765826

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