Abstract
SUMOylation, the modification of proteins with a small ubiquitin-like modifier (SUMO), is known to regulate various cellular events, including cell division. This process is dynamic, with its status depending on the balance between SUMOylation and deSUMOylation. While the regulation of cell division by sentrin-specific protease (SENP) family proteins through deSUMOylation has been investigated, the role of another deSUMOylase, deSUMOylating isopeptidase 1 (DESI1), remains unknown. In this study, we explored DESI1's role in cell division. Knockdown of DESI1 accelerated cell division progression, leading to a significant increase in abnormal chromosome segregation. These phenotypes were rescued by re-expression of wild-type DESI1, but not catalytically inactive DESI1. DESI1 knockdown reduced the mitotic arrest caused by nocodazole, suggesting DESI1's involvement in the spindle assembly checkpoint (SAC). Localization of Aurora B, a key SAC regulator, at the metaphase chromosomes was reduced due to decreased Aurora B expression upon DESI1 knockdown. Consistently, DESI1 knockdown reduced transcription of FoxM1 target genes, such as Aurora B, cyclin B1, and CENP-F. The TCGA database showed that both decreased and increased DESI1 expression levels are associated with poor prognosis in patients with certain cancer types. Importantly, we found that DESI1 knockdown reduced sensitivity to vincristine by inducing mitotic slippage. These results suggest that DESI1 is required for faithful chromosome segregation via regulating FoxM1 transcriptional activity and thereby SAC activity in an isopeptidase activity-dependent manner. Our findings identified DESI1 as a novel regulator of cell division and a factor affecting cancer chemotherapy.