The Deubiquitinating Enzyme USP14 Regulates Leukemic Chemotherapy Drugs-Induced Cell Apoptosis by Suppressing Ubiquitination of Aurora Kinase B

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.

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.

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.