Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating ?-catenin.

KRAS mutations are frequently detected in non-small cell lung cancers (NSCLCs). Although covalent KRASG12C inhibitors have been developed to treat KRASG12C-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven ...
cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of ?-catenin at lysine 508, which enhances the binding between ?-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.
Mesh Terms:
Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Humans, Lung Neoplasms, Mutation, Proto-Oncogene Proteins p21(ras), Ubiquitin-Specific Proteases, beta Catenin
Cell Rep
Date: Dec. 26, 2023
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