Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
Department of Pharmacology, Chosun University College of Medicine, Gwangju, South Korea.
Cancer Res. 2021 Mar 1;81(5):1321-1331. doi: 10.1158/0008-5472.CAN-20-1777. Epub 2020 Dec 22.
Deubiquitinating enzymes are increasingly recognized to play important roles in cancer, with many acting as oncogenes or tumor suppressors. In this study, we employed a bioinformatics approach to screen for enzymes from this family involved in cancer and found as a potent predictor of poor outcomes in neuroblastoma, an aggressive childhood cancer. resides in a region commonly deleted in neuroblastoma, yet was independently associated with poor outcomes in this disease. Deletion of in a murine model resulted in degradation of collapsin response mediator protein 2 (CRMP2), a regulator of axon growth, guidance, and neuronal polarity. Cells lacking USP24 had significant increases in spindle defects, chromosome missegregation, and aneuploidy, phenotypes that were rescued by the restoration of CRMP2. USP24 prevented aneuploidy by maintaining spindle-associated CRMP2, which is required for mitotic accuracy. Our findings further indicate that is a tumor suppressor that may play an important role in the pathogenesis of neuroblastoma. SIGNIFICANCE: This study identifies the chromosome instability gene as frequently deleted in neuroblastoma and provides important insight into the pathogenesis of this aggressive childhood cancer.
去泛素化酶在癌症中发挥着重要作用，越来越多的研究表明，许多去泛素化酶可以作为癌基因或肿瘤抑制因子。在这项研究中，我们采用生物信息学方法筛选参与癌症的酶家族成员，发现 USP24 是神经母细胞瘤不良预后的一个有效预测因子，这是一种侵袭性儿童癌症。USP24 位于神经母细胞瘤常见缺失区域，但与该疾病的不良预后独立相关。在鼠模型中敲除 USP24 会导致轴突生长、导向和神经元极性的调节因子 collapsin 反应介质蛋白 2 (CRMP2)降解。缺乏 USP24 的细胞纺锤体缺陷、染色体错分和非整倍体显著增加，这些表型可以通过恢复 CRMP2 来挽救。USP24 通过维持与纺锤体相关的 CRMP2 来防止非整倍体，而 CRMP2 是有丝分裂准确性所必需的。我们的研究结果进一步表明，USP24 是一种肿瘤抑制因子，可能在神经母细胞瘤的发病机制中发挥重要作用。意义：本研究鉴定出染色体不稳定基因 USP24 在神经母细胞瘤中经常缺失，并为这种侵袭性儿童癌症的发病机制提供了重要的见解。
