Objective：This study endeavors to elucidate the impact of small ubiquitin-related modifier (SUMO) modification on the protein levels and cellular localization of speckle type BTB/POZ protein (SPOP) and explore its implications in clear cell renal cell carcinoma (ccRCC). Methods：Using wild type (WT) and sentrin?specific proteases 1 (SENP1) knockout murine embryonic fibroblast (MEF) cells, we investigate the effects of Senp1 on Spop protein level and cellular localization. By comparing the protein expression levels of WT-Spop and its SUMO modification site mutants, the effects of SUMO modification on Spop protein levels were further confirmed. Proximity ligation assay (PLA) was employed to study the impact of WT-Spop and its SUMO modification site mutants on the binding ability with small ubiquitin-related modifier 1 (SUMO1). Finally, the correlation between SENP1 and SPOP in ccRCC was rigorously examined utilizing datasets and cell lines. Results：Senp1 knockout down-regulates the protein level and stability of Spop without affecting its nuclear cell localization. Mutating the SUMO modification site of Spop attenuated its binding affinity with Sumo1, consequently leading to diminished protein levels. Notably, the expression of SENP1 and SPOP exhibited a positive correlation in ccRCC. Conclusion：Senp1 stabilizes Spop protein through deSUMOylation modification, thereby underscoring a potential conservation of this regulatory mechanism in ccRCC.