Abstract
The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma.
Highlights
The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies
We found that X-linked inhibitor of apoptosis protein (XIAP) was the only candidate that displayed significant loss of mitotic expression in ubiquitin-specific protease 9X (USP9X)-silenced cells that was restored upon treatment with the proteasome inhibitor MG132, indicating a role for USP9X in proteasome-dependent mitotic stabilization of XIAP (Fig 1B and Appendix Fig S1A and B)
In further support of this notion, we found that both XIAP and USP9X display parallel accumulation in mitosis (Fig 1A)
Summary
The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies It has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. We set out to investigate the role of DUBs in the regulation of mitotic cell fate decisions These studies revealed a mitosis-specific function for the ubiquitin-specific protease 9X (USP9X), which we show to deubiquitylate and stabilize XIAP in order to promote mitotic survival. We demonstrate that loss of this anti-apoptotic pathway sensitizes cells to spindle poison-induced mitotic cell death independent of their MCL1 status and show that overexpression of USP9X and concomitant high expression of XIAP determine adverse prognosis and treatment resistance in human aggressive B-cell lymphomas
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