FKBP52 dictates the dual role of p53 in hepatocellular carcinoma: Mutation-specific prognostic stratification and therapeutic implications
TL;DR
These findings establish FKBP52 as a novel p53 stabilizer with context-dependent oncogenic effects, critically determined by p53 mutational status, and highlight the therapeutic potential of targeting the FKBP52-MDM2-p53 axis specifically in TP53-mutant HCC.
Abstract
The lack of mutation-contextual therapeutic targets remains a major barrier in hepatocellular carcinoma (HCC) management. Immunohistochemical analysis of 341 human HCC specimens identified FK506-binding protein 52 (FKBP52) as a tumor grade-associated biomarker. In vitro, FKBP52 overexpression enhanced proliferation in p53-mutant liver cancer cells but suppressed it in p53-wild-type cells. Using two murine models—subcutaneous xenografts and orthotopic liver implants—genetic manipulation confirmed that FKBP52 overexpression in Huh7 accelerated tumor growth, while shRNA-mediated knockdown attenuated growth and decreased AFP/CD133 expression. Differential p53 status underpinned this disparity. In vitro EdU incorporation assays, colony formation assays and TP53-null xenografts (Hep3B cells) demonstrated that p53 knockdown abrogated the phenotype, confirming that FKBP52 promotes mutant p53-driven tumorigenesis while suppressing wild-type p53 tumors. Mechanistically, co-immunoprecipitation (Co-IP) revealed FKBP52 binds p53 via its FK2 and TPR domains independently of mutation status. This interaction recruited MDM2 into the FKBP52-p53 complex, impairing MDM2-mediated degradation and prolonging stability of both wild-type and mutant p53. Taken together, our findings establish FKBP52 as a novel p53 stabilizer with context-dependent oncogenic effects, critically determined by p53 mutational status. These results highlight the therapeutic potential of targeting the FKBP52-MDM2-p53 axis specifically in TP53-mutant HCC.