<i>USP24</i> Is a Cancer-Associated Ubiquitin Hydrolase, Novel Tumor Suppressor, and Chromosome Instability Gene Deleted in Neuroblastoma.

Abstract

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 <i>USP24</i> as a potent predictor of poor outcomes in neuroblastoma, an aggressive childhood cancer. <i>USP24</i> resides in a region commonly deleted in neuroblastoma, yet was independently associated with poor outcomes in this disease. Deletion of <i>Usp24</i> 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 <i>USP24</i> is a tumor suppressor that may play an important role in the pathogenesis of neuroblastoma. SIGNIFICANCE: This study identifies the chromosome instability gene <i>USP24</i> as frequently deleted in neuroblastoma and provides important insight into the pathogenesis of this aggressive childhood cancer.