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Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis
Xuejie Gao1, Qilin Feng2, Qikai Zhang1
1Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
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.
Insights
Enolase 1 (ENO1) promotes multiple myeloma (MM) progression by enhancing mitophagy and YWHAZ protein stability, leading to drug resistance. Inhibiting ENO1 may reverse bortezomib resistance in MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Enolase 1 (ENO1) is a glycolytic enzyme with an unclear role beyond metabolism in multiple myeloma (MM).
- Understanding ENO1's function in MM pathophysiology is crucial for developing new therapeutic strategies.
- This study investigates ENO1's impact on mitophagy and bortezomib-induced apoptosis in MM.
Purpose of the Study:
- To elucidate the function of Enolase 1 (ENO1) in multiple myeloma (MM) pathogenesis.
- To investigate ENO1's role in regulating mitophagy and its impact on bortezomib-induced apoptosis.
- To explore ENO1 as a potential therapeutic target for overcoming drug resistance in MM.
Main Methods:
- Comparative analysis of ENO1 expression in MM patients and healthy donors.
- In silico analysis of ENO1 expression correlation with clinicopathological features and outcomes.
- In vivo and in vitro experiments including tumor models, co-immunoprecipitation, western blot, qPCR, immunohistochemistry, flow cytometry, and cell functional assays.
Main Results:
- ENO1 is an unfavorable prognostic factor in MM, suppressing tumorigenicity and causing cell cycle arrest upon knockdown.
- ENO1 promotes mitophagy by stabilizing YWHAZ protein, antagonizing its ubiquitination and increasing drug resistance.
- Combined treatment with bortezomib and ENO1 inhibitors shows synergistic anti-MM effects in vitro and in vivo.
Conclusions:
- ENO1 drives MM tumorigenesis and progression by activating mitophagy and conferring resistance to apoptosis and bortezomib.
- ENO1 enhances YWHAZ stability via acetylation, promoting mitophagy and inhibiting bortezomib-induced cell death.
- Targeting ENO1 represents a promising strategy to sensitize MM to bortezomib and overcome drug resistance.
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