Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation
Abstract Background Multiple Myeloma (MM) is the second most common hematological malignancy, characterized by the accumulation of monoclonal plasmocytes in the bone marrow. Despite advancements with proteasome inhibitors, immunomodulatory agents, and CD38-targeting antibodies, MM remains largely in...
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BMC
2024-12-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03241-2 |
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| author | Jessy Sirera Saharnaz Sarlak Manon Teisseire Alexandrine Carminati Victoria J. Nicolini Coline Savy Patrick Brest Thierry Juel Christophe Bontoux Marcel Deckert Mickael Ohanna Sandy Giuliano Maeva Dufies Gilles Pages Frederic Luciano |
| author_facet | Jessy Sirera Saharnaz Sarlak Manon Teisseire Alexandrine Carminati Victoria J. Nicolini Coline Savy Patrick Brest Thierry Juel Christophe Bontoux Marcel Deckert Mickael Ohanna Sandy Giuliano Maeva Dufies Gilles Pages Frederic Luciano |
| author_sort | Jessy Sirera |
| collection | DOAJ |
| description | Abstract Background Multiple Myeloma (MM) is the second most common hematological malignancy, characterized by the accumulation of monoclonal plasmocytes in the bone marrow. Despite advancements with proteasome inhibitors, immunomodulatory agents, and CD38-targeting antibodies, MM remains largely incurable due to resistant clones and frequent relapses. The success of the proteasome inhibitor bortezomib (BTZ) in MM treatment highlights the critical role of the ubiquitin–proteasome system (UPS) in this disease. Deubiquitinases (DUBs), which regulate protein stability, interactions, and localization by removing ubiquitin modifications, have emerged as promising therapeutic targets in various cancers, including MM. Methods Through a comprehensive loss-of-function screen, we identified USP39 as a critical survival factor for MM cells. Gene Set Enrichment Analysis (GSEA) was employed to correlate USP39 mRNA levels with clinical outcomes in MM patients. USP39 protein expression was evaluated via immunohistochemistry (IHC) on bone marrow samples from MM patients and healthy controls. The impact of USP39 knockdown via SiRNA was assessed through in vitro assays measuring cellular metabolism, clonogenic capacity, cell cycle progression, apoptosis, and sensitivity to BTZ. Co-immunoprecipitation and deubiquitination assays were conducted to elucidate the interaction and regulation of ZEB1 by USP39. Finally, in vitro and in vivo zebrafish experiments were used to characterize the biological consequences of ZEB1 regulation by USP39. Results Our study found that elevated USP39 mRNA levels are directly associated with shorter survival in MM patients. USP39 protein expression is significantly higher in MM patient plasmocytes compared to healthy individuals. USP39 knockdown inhibits clonogenic capacity, induces cell cycle arrest, triggers apoptosis, and overcomes BTZ resistance. Gain-of-function assays revealed that USP39 stabilizes the transcription factor ZEB1, enhancing the proliferation and the trans-migratory potential of MM cells. Conclusions Our findings highlight the critical role of the deubiquitinase USP39, suggesting that the USP39/ZEB1 axis could serve as a potential diagnostic marker and therapeutic target in MM. |
| format | Article |
| id | doaj-art-165d942d328a4b46ae5e0b3499c025bc |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-165d942d328a4b46ae5e0b3499c025bc2025-01-05T12:50:05ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662024-12-0143112110.1186/s13046-024-03241-2Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradationJessy Sirera0Saharnaz Sarlak1Manon Teisseire2Alexandrine Carminati3Victoria J. Nicolini4Coline Savy5Patrick Brest6Thierry Juel7Christophe Bontoux8Marcel Deckert9Mickael Ohanna10Sandy Giuliano11Maeva Dufies12Gilles Pages13Frederic Luciano14Institute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurCentre Méditerranéen de Médecine Moléculaire (C3M), INSERM, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurCentre Méditerranéen de Médecine Moléculaire (C3M), INSERM, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurLaboratory of Clinical and Experimental Pathology, University Côte d’Azur, Pasteur Hospital, Hospital-integrated Biobank (BB-0033-00025), FHU OncoAge, IHU RespirERA, Centre Hospitalier Universitaire de NiceCentre Méditerranéen de Médecine Moléculaire (C3M), INSERM, University Côte d’AzurCentre Méditerranéen de Médecine Moléculaire (C3M), INSERM, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurInstitute for Research On Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U1081, University Côte d’AzurAbstract Background Multiple Myeloma (MM) is the second most common hematological malignancy, characterized by the accumulation of monoclonal plasmocytes in the bone marrow. Despite advancements with proteasome inhibitors, immunomodulatory agents, and CD38-targeting antibodies, MM remains largely incurable due to resistant clones and frequent relapses. The success of the proteasome inhibitor bortezomib (BTZ) in MM treatment highlights the critical role of the ubiquitin–proteasome system (UPS) in this disease. Deubiquitinases (DUBs), which regulate protein stability, interactions, and localization by removing ubiquitin modifications, have emerged as promising therapeutic targets in various cancers, including MM. Methods Through a comprehensive loss-of-function screen, we identified USP39 as a critical survival factor for MM cells. Gene Set Enrichment Analysis (GSEA) was employed to correlate USP39 mRNA levels with clinical outcomes in MM patients. USP39 protein expression was evaluated via immunohistochemistry (IHC) on bone marrow samples from MM patients and healthy controls. The impact of USP39 knockdown via SiRNA was assessed through in vitro assays measuring cellular metabolism, clonogenic capacity, cell cycle progression, apoptosis, and sensitivity to BTZ. Co-immunoprecipitation and deubiquitination assays were conducted to elucidate the interaction and regulation of ZEB1 by USP39. Finally, in vitro and in vivo zebrafish experiments were used to characterize the biological consequences of ZEB1 regulation by USP39. Results Our study found that elevated USP39 mRNA levels are directly associated with shorter survival in MM patients. USP39 protein expression is significantly higher in MM patient plasmocytes compared to healthy individuals. USP39 knockdown inhibits clonogenic capacity, induces cell cycle arrest, triggers apoptosis, and overcomes BTZ resistance. Gain-of-function assays revealed that USP39 stabilizes the transcription factor ZEB1, enhancing the proliferation and the trans-migratory potential of MM cells. Conclusions Our findings highlight the critical role of the deubiquitinase USP39, suggesting that the USP39/ZEB1 axis could serve as a potential diagnostic marker and therapeutic target in MM.https://doi.org/10.1186/s13046-024-03241-2Multiple myelomaDeubiquitinaseUSP39ZEB1Migration |
| spellingShingle | Jessy Sirera Saharnaz Sarlak Manon Teisseire Alexandrine Carminati Victoria J. Nicolini Coline Savy Patrick Brest Thierry Juel Christophe Bontoux Marcel Deckert Mickael Ohanna Sandy Giuliano Maeva Dufies Gilles Pages Frederic Luciano Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation Journal of Experimental & Clinical Cancer Research Multiple myeloma Deubiquitinase USP39 ZEB1 Migration |
| title | Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation |
| title_full | Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation |
| title_fullStr | Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation |
| title_full_unstemmed | Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation |
| title_short | Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation |
| title_sort | disrupting usp39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through zeb1 degradation |
| topic | Multiple myeloma Deubiquitinase USP39 ZEB1 Migration |
| url | https://doi.org/10.1186/s13046-024-03241-2 |
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