Abstract
Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of RCC. C8orf76 is upregulated in multiple cancers and linked to malignant progression, but its role in ccRCC remains unclear. Here, we explored the function and mechanism of C8orf76 in ccRCC using in vitro, in vivo, RNA-sequencing, and bioinformatic analyses. We found that C8orf76 and CALB2 were highly expressed in ccRCC and associated with poor prognosis. C8orf76 knockdown inhibited ccRCC proliferation and migration in vitro and in vivo by inducing G1 cell-cycle arrest and cellular senescence via downregulating CALB2, which could be partially reversed by CALB2 overexpression. Similarly, CALB2 knockdown induces cell-cycle arrest and cellular senescence in ccRCC, thereby inhibiting cell proliferation and migration. These effects are partially reversed by additional CDKN2A knockdown. Therefore, C8orf76 directly binds to the CALB2 promoter to activate its transcription. The C8orf76/CALB2 axis promotes ccRCC progression by repressing cellular senescence.