Wu Yunfei, Xu Zhijie, Wang Runzhe, Bai Yanfeng, Chen Xiaoyi, Cheng Cheng, Jin Baiye, Fu Guanghou
Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treat-ment, Hangzhou 310024, China.
Department of pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Transl Oncol. 2025 May;55:102370. doi: 10.1016/j.tranon.2025.102370. Epub 2025 Mar 22.
Deubiquitinating enzymes (DUBs) significantly contribute to tumor progression and treatment resistance in bladder cancer. However, the mechanisms by which DUBs promote malignant behavior in patients with bladder cancer remain poorly understood. Using online databases such as TCGA, GSE13507, and GSE23894, along with clinical sample validation, the expression profiles of PSMD14 in patients with bladder cancer were identified. The analysis revealed correlations among PSMD14, nucleolin (NCL), and YAP1, which were verified using TCGA data and clinical sample studies. In this study, PSMD14 was identified as a novel DUB involved in bladder cancer malignancy. PSMD14 expression is upregulated in the tissues of patients with bladder cancer and is associated with poor clinical outcomes. Both in vitro and in vivo experiments demonstrated that PSMD14 inhibition significantly reduced bladder cancer cell proliferation, metastasis, and cisplatin resistance. Mechanistic investigations revealed that PSMD14 enhances protein stability and NCL expression through deubiquitination. NCL, an RNA-binding protein, exerts oncogenic effects in patients with bladder cancer by binding to and stabilizing YAP1 mRNA, leading to increased YAP1 expression and activation of downstream YAP1-related pathways. Notably, the tumor-suppressive effects of PSMD14 inhibition were partially reversed by the overexpression of either NCL or YAP1. In conclusion, the PSMD14/NCL/YAP1 axis plays a pivotal role in the malignant behavior of bladder cancer, including proliferation, metastasis, and chemoresistance. These findings suggest that PSMD14 is a critical biomarker for predicting bladder cancer prognosis and is a potential target for therapeutic interventions.
去泛素化酶（DUBs）在膀胱癌的肿瘤进展和治疗耐药中发挥着重要作用。然而，DUBs促进膀胱癌患者恶性行为的机制仍不清楚。通过使用TCGA、GSE13507和GSE23894等在线数据库，并结合临床样本验证，确定了膀胱癌患者中PSMD14的表达谱。分析揭示了PSMD14、核仁素（NCL）和YAP1之间的相关性，并通过TCGA数据和临床样本研究得到了验证。在本研究中，PSMD14被确定为一种参与膀胱癌恶性进展的新型DUB。PSMD14在膀胱癌患者组织中的表达上调，且与不良临床结局相关。体外和体内实验均表明，抑制PSMD14可显著降低膀胱癌细胞的增殖、转移和顺铂耐药性。机制研究表明，PSMD14通过去泛素化增强蛋白质稳定性和NCL表达。NCL是一种RNA结合蛋白，通过与YAP1 mRNA结合并使其稳定，在膀胱癌患者中发挥致癌作用，导致YAP1表达增加和下游YAP1相关通路的激活。值得注意的是，NCL或YAP1的过表达部分逆转了PSMD14抑制的肿瘤抑制作用。总之，PSMD14/NCL/YAP1轴在膀胱癌的恶性行为（包括增殖、转移和化疗耐药）中起关键作用。这些发现表明，PSMD14是预测膀胱癌预后的关键生物标志物，也是治疗干预的潜在靶点。
