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

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 deubiquit...

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Published in:EMBO molecular medicine Vol. 8; no. 8; pp. 851 - 862
Main Authors: Engel, Katharina, Rudelius, Martina, Slawska, Jolanta, Jacobs, Laura, Ahangarian Abhari, Behnaz, Altmann, Bettina, Kurutz, Julia, Rathakrishnan, Abirami, Fernández‐Sáiz, Vanesa, Brunner, Andrä, Targosz, Bianca‐Sabrina, Loewecke, Felicia, Gloeckner, Christian Johannes, Ueffing, Marius, Fulda, Simone, Pfreundschuh, Michael, Trümper, Lorenz, Klapper, Wolfram, Keller, Ulrich, Jost, Philipp J, Rosenwald, Andreas, Peschel, Christian, Bassermann, Florian
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01.08.2016
EMBO Press
John Wiley and Sons Inc
Springer Nature
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis
B-cell lymphoma
B-Lymphocytes - drug effects
B-Lymphocytes - physiology
Cancer therapies
Cell cycle
Cell Death
Cell fate
Cells, Cultured
Chemoresistance
Chemotherapy
Chromosomes
Disease Models, Animal
Drug Resistance
EMBO03
EMBO18
Genomes
Humans
IAP protein
Lymphocytes B
Lymphoma
Lymphoma, B-Cell - pathology
Medical prognosis
Mice
Mitosis
Myc protein
Protein Processing, Post-Translational
Proteins
Therapeutic applications
Tumors
ubiquitin
Ubiquitin - metabolism
Ubiquitin Thiolesterase - metabolism
USP9X
X-Linked Inhibitor of Apoptosis Protein - metabolism
XIAP
XIAP protein
United Kingdom > UK
XIAP
mitosis
USP9X
B‐cell lymphoma
ubiquitin
ISSN:1757-4676, 1757-4684, 1757-4684
Online Access:Get full text
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Summary: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. Synopsis USP9X deubiquitylates and stabilizes anti‐apoptotic protein XIAP and promotes mitotic survival. Overexpression of USP9X/XIAP confers chemotherapy resistance and associates with decreased survival in aggressive B‐cell lymphoma patients. USP9X deubiquitylates and stabilizes XIAP in mitosis The USP9X‐XIAP pathway promotes mitotic survival USP9X and XIAP are overexpressed in Diffuse Large B Cell Lymphoma (DLBCL) The USP9X‐XIAP axis promotes lymphoma growth and resistance to spindle poisons Overexpression of USP9X and XIAP associates with chemotherapy resistance in DLBCL patients Graphical Abstract USP9X deubiquitylates and stabilizes anti‐apoptotic protein XIAP and promotes mitotic survival. Overexpression of USP9X/XIAP confers chemotherapy resistance and associates with decreased survival in aggressive B‐cell lymphoma patients.
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ISSN:1757-4676
1757-4684
1757-4684
DOI:10.15252/emmm.201506047