USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B‐cell lymphoma

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.

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

“…Analysis of our cohort and publicly available databases revealed recurrent loss-of-function mutations in USP9X. This finding was surprising because USP9X is perceived mainly as an oncogene in solid tumors and in BCP-ALL and B-cell lymphoblastic lymphomas (37,40,51,52). Because USP9X is a deubiquitinase, its effect on tumor growth should largely be dependent on its substrates, which probably explains its ascribed role as tumor suppressor in pancreatic cancer (53).…”

Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis

“…Based on protein complex purification coupled with mass spectrometry, we have demonstrated that XIAP is a target of USP11, wherein USP11 directly binds to XIAP through Leu207 on XIAP and stabilizes it by deubiquitylation of XIAP. Very recently, it was reported that the XIAP protein levels could be also regulated by USP9x in small fraction of mitotic population (Engel et al, 2016) (Supplemental Fig. 1).…”

“…DUB is a counteracting component of the ubiquitin-proteasomal system that together with ubiquitin-protein ligase regulates protein stability as well as subcellular localization of protein (Clague et al, 2013, Engel et al, 2016). DUB regulates protein function through several mechanisms, including direct binding to substrate and removing ubiquitin-chain from its target, modulating ubiquitin conjugating enzyme E2, counteracting ubiquitin E3 ligase and assisting proteasomal function (Clague et al, 2013, Engel et al, 2016).…”

“…DUB regulates protein function through several mechanisms, including direct binding to substrate and removing ubiquitin-chain from its target, modulating ubiquitin conjugating enzyme E2, counteracting ubiquitin E3 ligase and assisting proteasomal function (Clague et al, 2013, Engel et al, 2016). Several DUBs have been recently reported to be critical in tumorigenesis-related cellular processes (Ramakrishna et al, 2011, Wu et al, 2013, Popov et al, 2007, Schwickart et al, 2010).…”

The Synthetic β-Nitrostyrene Derivative CYT-Rx20 Inhibits Esophageal Tumor Growth and Metastasis via PI3K/AKT and STAT3 Pathways

“…In addition, no obvious expression of cleaved caspase-3 was observed in the esophageal epithelium of control or CYT-Rx20-administered mice. Of note, mouse lymph node tissue was used as the positive control to assess the levels of cleaved caspase-3 [28,29] and were depicted in S3 Fig.…”