Aims
Aurora kinase B is a mitotic checkpoint kinase that plays a pivotal role in mitosis by ensuring correct chromosome segregation and normal progression through mitosis. Aurora B has been found to be amplified and overexpressed in several types of leukemia. The deubiquitinating enzyme USP14 is one of three proteasome-associated deubiquitinating enzymes and plays critical roles in diverse biological processes including cancer. However, whether USP14 has a role in leukemia cells remains elusive.
Background/aims
Aurora kinase B is a mitotic checkpoint kinase that plays a pivotal role in mitosis by ensuring correct chromosome segregation and normal progression through mitosis. Aurora B has been found to be amplified and overexpressed in several types of leukemia. The deubiquitinating enzyme USP14 is one of three proteasome-associated deubiquitinating enzymes and plays critical roles in diverse biological processes including cancer. However, whether USP14 has a role in leukemia cells remains elusive.
Conclusion
Thus, our data suggest that USP14 plays a novel critical role of in leukemia cells apoptosis through Aurora B stabilization and USP14 could be a potential therapeutic target for leukemia.
Methods
Leukemic U937, NB4 and Jurkat cells were treated with diverse apoptosis-inducing drugs. The interaction between USP14 and Aurora B were determined by Western blot. The effect of USP14 in the regulation of Aurora B was detected by cycloheximide (CHX) and deubiquitination assays. FACS assay was used to determine the apoptosis ratio of cells after treatments.
Results
We found that Aurora B was ubiquitinated and degraded during leukemic chemotherapy drugs-induced cell apoptosis. FBXW7 mediated Aurora B ubiquitination and degradation during chemotherapeutic drugs-induced apoptosis. USP14 associated with Aurora B and prevented Aurora B degradation. Functionally, overexpression of USP14 inhibits chemotherapeutic drugs-induced apoptosis in leukemia cells. On the contrary, administration of b-AP15, a specific inhibitor of USP14, significantly increased leukemia cells apoptosis in a dose-dependent manner.