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

Ubiquitin‐specific peptidase 24 accelerates aerobic glycolysis and tumor progression in gastric carcinoma through stabilizing PLK1 to activate NOTCH1

“…As an ubiquitin‐specific protease, USP24 plays an important role in many diseases 17,20,35–37 . We explored its role in GC, and found that USP24 is highly expressed in GC, and the high expression of USP24 is closely related to the prognosis of GC patients.…”

“…As an ubiquitin‐specific protease, USP24 plays an important role in many diseases. 17 , 20 , 35 , 36 , 37 We explored its role in GC, and found that USP24 is highly expressed in GC, and the high expression of USP24 is closely related to the prognosis of GC patients. In terms of its mechanisms, USP24 enhances the stability of PLK1 through deubiquitination and upregulates the glycolysis of cells, thus promoting the pathological process in GC.…”

Identification of hepatocellular carcinoma-related subtypes and development of a prognostic model: a study based on ferritinophagy-related genes

“…However, it was remarkably increased in the FRG mutation group than in the non-mutation group. High-mutation frequency genes, such as FRGs like HERC2 and USP24, have been linked to the onset and progression of various malignancies [ 62 – 65 ]. However, the relevance of these genes to LIHC needs to be explored in further studies.…”

Chromosome instability in neuroblastoma: A pathway to aggressive disease

“…Our screen focussed on the gene family encoding de-ubiquitinating enzymes (DUBs) – as these are emerging as novel therapeutic targets. When examining the impact of 95 DUBs on outcomes in NBL, we found that reduced expression of USP24 had the largest impact on outcomes, with a z-score of -10.14 (0.38 percentile) suggesting that USP24 reductions have a powerful negative impact in this disease ( 67 ). For comparison, the canonical NBL oncogene MYCN has a z-score of +8.18 (97.34 percentile) - in line with the known relationship between high expression and aggressive disease.…”

“…USP24 is encoded on chromosome 1p32.3 – and area of the genome that is frequently lost in neuroblastoma tumors ( 68 , 69 ). It is notable then, that cells lacking USP24 have a significant increase in erroneous mitosis, with a particular increase in lagging chromosomes ( 67 ). These cells and tissues from mice missing even 1 copy of the Usp24 gene have a significant increase in numerical chromosome aneuploidy.…”