Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis
Abstract Background Enolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its...
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2025-01-01
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| Online Access: | https://doi.org/10.1186/s12929-024-01101-x |
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| author | Xuejie Gao Qilin Feng Qikai Zhang Yifei Zhang Chaolu Hu Li Zhang Hui Zhang Guanli Wang Ke Hu Mengmeng Ma Zhuning Wang Yujie Liu Dong An Hongfei Yi Yu Peng Xiaosong Wu Gege Chen Xinyan Jia Haiyan Cai Jumei Shi |
| author_facet | Xuejie Gao Qilin Feng Qikai Zhang Yifei Zhang Chaolu Hu Li Zhang Hui Zhang Guanli Wang Ke Hu Mengmeng Ma Zhuning Wang Yujie Liu Dong An Hongfei Yi Yu Peng Xiaosong Wu Gege Chen Xinyan Jia Haiyan Cai Jumei Shi |
| author_sort | Xuejie Gao |
| collection | DOAJ |
| description | Abstract Background Enolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its impact on mitophagy under bortezomib-induced apoptosis. Methods The bone marrow of clinical MM patients and healthy normal donors was used to compare the expression level of ENO1. Using online databases, we conducted an analysis to examine the correlation between ENO1 expression and both clinicopathological characteristics and patient outcomes. To investigate the biological functions of ENO1 in MM and the underlying molecular mechanisms involved, we conducted the following experiment: construction of a subcutaneous graft tumor model, co-immunoprecipitation, western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and cell functional assays. Results ENO1 was identified as an unfavorable prognostic factor in MM. ENO1 knockdown suppresses tumorigenicity and causes cell cycle arrest. Inhibition of ENO1-regulated mitophagy sensitizes tumor cells to apoptosis. ENO1 enhanced the stability of the YWHAZ protein by increasing the acetylation of lysine in YWHAZ while antagonizing its ubiquitination, which in turn promoted mitophagy. HDAC6 mediates the deacetylation of YWHAZ by deacetylating the K138 site of YWHAZ. Inhibition of HDAC6 increased YWHAZ acetylation and decreased YWHAZ ubiquitination. Furthermore, combination treatment with bortezomib and pharmaceutical agents targeting ENO1 has synergistic anti-MM effects both in vivo and in vitro. Conclusion Our data suggest that ENO1 promotes MM tumorigenesis and progression. ENO1 activates mitophagy by promoting the stability of YWHAZ and inhibits apoptosis and thus, leads to the drug resistance. ENO1-dependent mitophagy promotes MM proliferation and suppresses the level of bortezomib-induced apoptosis. Inhibition of ENO1 may represent a potential strategy to reverse the resistance of MM to bortezomib. |
| format | Article |
| id | doaj-art-59ee53127b5647ccb78fd39ae0556aee |
| institution | Kabale University |
| issn | 1423-0127 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Journal of Biomedical Science |
| spelling | doaj-art-59ee53127b5647ccb78fd39ae0556aee2025-01-26T12:46:16ZengBMCJournal of Biomedical Science1423-01272025-01-0132112010.1186/s12929-024-01101-xTargeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axisXuejie Gao0Qilin Feng1Qikai Zhang2Yifei Zhang3Chaolu Hu4Li Zhang5Hui Zhang6Guanli Wang7Ke Hu8Mengmeng Ma9Zhuning Wang10Yujie Liu11Dong An12Hongfei Yi13Yu Peng14Xiaosong Wu15Gege Chen16Xinyan Jia17Haiyan Cai18Jumei Shi19Department of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Affiliated Hospital of Nantong UniversityDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineDepartment of Hematology, Shanghai East Hospital, Tongji University School of MedicineAbstract Background Enolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its impact on mitophagy under bortezomib-induced apoptosis. Methods The bone marrow of clinical MM patients and healthy normal donors was used to compare the expression level of ENO1. Using online databases, we conducted an analysis to examine the correlation between ENO1 expression and both clinicopathological characteristics and patient outcomes. To investigate the biological functions of ENO1 in MM and the underlying molecular mechanisms involved, we conducted the following experiment: construction of a subcutaneous graft tumor model, co-immunoprecipitation, western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and cell functional assays. Results ENO1 was identified as an unfavorable prognostic factor in MM. ENO1 knockdown suppresses tumorigenicity and causes cell cycle arrest. Inhibition of ENO1-regulated mitophagy sensitizes tumor cells to apoptosis. ENO1 enhanced the stability of the YWHAZ protein by increasing the acetylation of lysine in YWHAZ while antagonizing its ubiquitination, which in turn promoted mitophagy. HDAC6 mediates the deacetylation of YWHAZ by deacetylating the K138 site of YWHAZ. Inhibition of HDAC6 increased YWHAZ acetylation and decreased YWHAZ ubiquitination. Furthermore, combination treatment with bortezomib and pharmaceutical agents targeting ENO1 has synergistic anti-MM effects both in vivo and in vitro. Conclusion Our data suggest that ENO1 promotes MM tumorigenesis and progression. ENO1 activates mitophagy by promoting the stability of YWHAZ and inhibits apoptosis and thus, leads to the drug resistance. ENO1-dependent mitophagy promotes MM proliferation and suppresses the level of bortezomib-induced apoptosis. Inhibition of ENO1 may represent a potential strategy to reverse the resistance of MM to bortezomib.https://doi.org/10.1186/s12929-024-01101-xMultiple myelomaENO1MitophagyYWHAZChemoresistance |
| spellingShingle | Xuejie Gao Qilin Feng Qikai Zhang Yifei Zhang Chaolu Hu Li Zhang Hui Zhang Guanli Wang Ke Hu Mengmeng Ma Zhuning Wang Yujie Liu Dong An Hongfei Yi Yu Peng Xiaosong Wu Gege Chen Xinyan Jia Haiyan Cai Jumei Shi Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis Journal of Biomedical Science Multiple myeloma ENO1 Mitophagy YWHAZ Chemoresistance |
| title | Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis |
| title_full | Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis |
| title_fullStr | Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis |
| title_full_unstemmed | Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis |
| title_short | Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis |
| title_sort | targeting enolase 1 reverses bortezomib resistance in multiple myeloma through ywhaz parkin axis |
| topic | Multiple myeloma ENO1 Mitophagy YWHAZ Chemoresistance |
| url | https://doi.org/10.1186/s12929-024-01101-x |
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