The deubiquitinase YOD1 suppresses tumor progression by stabilizing ZNF24 in clear cell renal carcinoma

Metastasis remains a significant challenge in the management of clear cell renal cell carcinoma (ccRCC), and a continued focus on its underlying mechanisms is crucial for improving patient outcomes and optimizing clinical therapies. The ovarian-tumor related protease (OTU) is involved in regulating critical cell signaling pathways, but the functions of most OTUs have yet to be explored. In this study, an unbiased RNAi screening revealed that ovarian tumor domain-containing 2 (YOD1) knockdown significantly promoted cell metastasis. YOD1 downregulation promoted ccRCC growth and metastasis both in vitro and in vivo. Notably, YOD1 knockdown stimulated the growth of organoids derived from ccRCC patients. Further investigation revealed that YOD1 directly interacted with and stabilized Zinc finger protein 24 (ZNF24) expression by deubiquitination in a manner dependent on its catalytic activity. YOD1 inhibition attenuated ZNF24 transcriptional repression of vascular endothelial growth factor A (VEGFA), thereby promoting VEGFA gene expression. Furthermore, ZNF24 was identified as a key mediator of YOD1 function. The expression of YOD1 and ZNF24 was significantly downregulated in tumor tissues, with a strong correlation between them. Importantly, reduced YOD1 and ZNF24 levels were strongly associated with poor clinical outcomes in ccRCC patients. Our results reveal the mechanism by which YOD1 regulates VEGFA transcription and suppresses tumorigenesis by deubiquitinating ZNF24, providing a therapeutic target in ccRCC.