2. Academic Validation
  3. The deubiquitinase YOD1 suppresses tumor progression by stabilizing ZNF24 in clear cell renal carcinoma

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

  • Cell Death Dis. 2025 Apr 24;16(1):334. doi: 10.1038/s41419-025-07673-2.
Ji Liu # 1 2,  Ying Lu # 3,  Runye Zhu 1 2,  Ping Xi 4,  Zhihao Yang 1 2,  Zhipeng Zhang 1 2,  Yunbing Xiong 1 2,  Yifu Liu 5,  Qiqi Zhu 1 2,  Ting Sun 6 7,  Wenjie Xie 8 9,  Binbin Gong 10 11
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 2 Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang City, Jiangxi Province, China.
  • 3 Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 4 Department of Thoracic Surgery, XinSteel Center Hospital, Xinyu, China.
  • 5 The Second Affiliated Hospital, Department of Urology, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
  • 6 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. 361439919033@email.ncu.edu.cn.
  • 7 Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang City, Jiangxi Province, China. 361439919033@email.ncu.edu.cn.
  • 8 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. ndyfy04140@ncu.edu.cn.
  • 9 Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang City, Jiangxi Province, China. ndyfy04140@ncu.edu.cn.
  • 10 Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China. ndyfy05944@ncu.edu.cn.
  • 11 Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang City, Jiangxi Province, China. ndyfy05944@ncu.edu.cn.
  • # Contributed equally.
PMID: 40274778 DOI: 10.1038/s41419-025-07673-2
Abstract

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.

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