Fused in Sarcoma (FUS) promotes renal cell carcinoma progression via the KCMF1/FUS/CENPT axis and activation of the JNK signaling pathway.

OBJECTIVE: Fused in Sarcoma (FUS), an RNA-binding protein implicated in gene expression regulation and DNA damage repair, demonstrates abnormal overexpression in multiple malignancies. Its functional significance in Renal Cell Carcinoma (RCC) pathogenesis remains poorly characterized. METHODS: We employed bioinformatics analysis to assess FUS prognostic value, complemented by in vitro and in vivo functional studies to evaluate its phenotypic impact on RCC. Protein interactors were identified through Co-Immunoprecipitation (Co-IP), with mechanistic insights derived from flow cytometry and immunofluorescence assays. RESULTS: Clinical RCC specimens exhibited significantly elevated FUS expression compared to adjacent normal tissues (p < 0.01). Both cellular models and xenograft experiments demonstrated that FUS overexpression potentiated RCC proliferation, invasion, and metastatic capacity, whereas FUS knockdown suppressed tumorigenic progression. Mechanistically, FUS promoted RCC advancement by attenuating apoptosis and inducing Epithelial-Mesenchymal Transition (EMT). Further investigation revealed FUS interaction with KCMF1 and CENPT, forming a pro-oncogenic signaling axis. KCMF1 overexpression facilitated FUS nuclear translocation, enhancing its binding to CENPT mRNA and subsequent CENPT upregulation. As a core centromere protein, the upregulation of CENPT can induce abnormal chromosome segregation, leading to genomic instability. This feature is associated with a higher recurrence rate, shorter survival time, and distant metastasis in RCC patients. The JNK (c-Jun N-terminal Kinase) signaling also plays a key role in driving malignant progression. CONCLUSION: The KCMF1/FUS/CENPT axis promotes RCC growth and metastasis via a non-proteasomal mechanism coupled with JNK pathway activation. These findings position FUS as a potential diagnostic biomarker and therapeutic target in RCC management.