BAP1 deficiency-induced SKA3 promotes clear cell renal cell carcinoma malignant progression by regulating chromosomal instability.

Chromosomal instability (CIN), a hallmark of malignancy, remains poorly understood in clear cell renal cell carcinoma (ccRCC). Here, we identify spindle and kinetochore-associated protein 3 (SKA3) as a critical regulator of CIN in ccRCC. BAP1 loss-of-function mutations, prevalent in ccRCC, drive aberrant SKA3 overexpression. Mechanistically, BAP1 deubiquitinates nuclear receptor co-repressor 1 (NCOR1) to enhance its recruitment to the SKA3 promoter, thereby repressing SKA3 transcription. Additionally, BAP1-mediated histone H2AK119 deubiquitination at the TRIM25 promoter activates the expression of TRIM25, facilitating ubiquitin-proteasome-mediated degradation of SKA3. BAP1 deficiency disrupts both regulatory pathways, leading to aberrant accumulation of SKA3, which fuels CIN and correlates with metastasis progression and poor prognosis. In conclusion, our findings establish dysfunction of the BAP1-SKA3 axis as a molecular driver of CIN in ccRCC and suggest SKA3 as a potential therapeutic target for BAP1-mutant ccRCC.