Wei Xiaosong, Wang Beibei, Yang Yang, Fang Zhiwei, Yi Chengzhi, Zhang Liuhui, Fan Xin, Tang Dongdong, Zhang Lirong, Yang Xiaoming, Song Dongkui
Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Oncogene. 2025 May 28. doi: 10.1038/s41388-025-03450-9.
Zinc finger protein 24 (ZNF24) is a conserved multifunctional transcription factor associated with tumorigenesis, but its function in bladder carcinogenesis remains unclear. Herein, the expression of ZNF24 was decreased in bladder cancer (BC) cells and tissues, and patients with higher expression of ZNF24 had a better prognosis. Doxycycline-induced overexpression and knockdown of ZNF24 identified its anti-proliferative and anti-metastasis role in BC in vitro and in vivo. The potential genes for the anti-cancer role of ZNF24, involving transcriptional regulation of several factors, such as dual-specificity phosphatase 1 and squalene epoxidase. E2 conjugating enzyme UBC9 and small ubiquitin-like modifier (SUMO) 1 were found to interact with ZNF24, suggesting that ZNF24 may be SUMOylated. Consistent with the expression, ZNF24 SUMOylation levels were decreased in BC cells and tissues. Pan-SUMOylation inhibition promoted protein degradation of ZNF24. UBC9 SUMOylated ZNF24 at Lys-27 (K27) site with SUMO1 modification and the K27 mutation of ZNF24 greatly damaged the protein stability of ZNF24. Cullin 3 (CUL3), a E3 ubiquitin ligase, was responsible for the degradation of ZNF24. ZNF24 SUMOylation prevented CUL3-mediated protein degradation of ZNF24. Overall, the crosstalk between the SUMOylation and ubiquitination of ZNF24 may be a novel regulatory mechanism to block tumorigenesis and development of BC.
锌指蛋白24（ZNF24）是一种与肿瘤发生相关的保守多功能转录因子，但其在膀胱癌发生中的作用仍不清楚。在此，ZNF24在膀胱癌细胞和组织中的表达降低，ZNF24表达较高的患者预后较好。强力霉素诱导的ZNF24过表达和敲低确定了其在体外和体内对膀胱癌的抗增殖和抗转移作用。ZNF24抗癌作用的潜在基因，涉及对多种因子的转录调控，如双特异性磷酸酶1和角鲨烯环氧化酶。发现E2共轭酶UBC9和小泛素样修饰物（SUMO）1与ZNF24相互作用，表明ZNF24可能被SUMO化。与表达情况一致，ZNF24的SUMO化水平在膀胱癌细胞和组织中降低。泛SUMO化抑制促进了ZNF24的蛋白质降解。UBC9在赖氨酸-27（K27）位点将ZNF24 SUMO化并伴有SUMO1修饰，ZNF24的K27突变极大地破坏了ZNF24的蛋白质稳定性。E3泛素连接酶Cullin 3（CUL3）负责ZNF24的降解。ZNF24的SUMO化阻止了CUL3介导的ZNF24蛋白质降解。总体而言，ZNF24的SUMO化和泛素化之间的相互作用可能是一种阻断膀胱癌发生和发展的新型调控机制。
