CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation
Abstract Aims Doxorubicin (DOX) is a potent anticancer drug; however, it is associated with significant cardiotoxicity. CDC20 is an E3 ubiquitin ligase that plays a role in cell cycle progression and apoptosis in various types of cancers. The involvement of CDC20 in DOX-induced cardiotoxicity (DIC)...
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BMC
2025-03-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00708-8 |
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| author | Zhenyu Feng Ningning Zhang Liang Wang Xumin Guan Yunpeng Xie Yun-long Xia |
| author_facet | Zhenyu Feng Ningning Zhang Liang Wang Xumin Guan Yunpeng Xie Yun-long Xia |
| author_sort | Zhenyu Feng |
| collection | DOAJ |
| description | Abstract Aims Doxorubicin (DOX) is a potent anticancer drug; however, it is associated with significant cardiotoxicity. CDC20 is an E3 ubiquitin ligase that plays a role in cell cycle progression and apoptosis in various types of cancers. The involvement of CDC20 in DOX-induced cardiotoxicity (DIC) is poorly understood. Hence, this study aimed to explore the potential role of CDC20 in the development of DIC and assess whether CDC20 influences the antitumor effects of DOX. Methods and results H9C2 cells were treated with DOX, followed by transcriptomic analysis to identify differentially expressed genes. C57BL/6 mice were treated with DOX for 4 weeks after tail vein injection of CDC20 myocardial-specific knockout mice, AAV9-cTNT-(si) CDC20, or intraperitoneal injection of apcin. Cardiac function and pathological changes were evaluated by echocardiography and pathological staining, respectively. The influence of CDC20 on DOX-induced tumor inhibition was assessed in tumor-bearing mice. In vitro analysis involved treating cardiomyocytes with the Ad-CDC20 adenovirus and DOX, followed by proteomic and ubiquitination-related assays to identify potential downstream ubiquitinated CDC20 proteins. Additionally, we investigated the effect of CCDC69 on CDC20-mediated protection against DOX-induced apoptosis using CCDC69 shRNA. Transcriptome analysis revealed that DOX effectively suppressed the expression of CDC20. Cardiomyocyte-specific overexpression of CDC20 in a DOX-induced mouse model of myocardial injury effectively mitigated cardiomyocyte apoptosis, inflammation, fibrosis, and cell atrophy. Our mechanistic investigation revealed that CDC20 attenuates DOX-induced apoptosis by downregulating CCDC69 expression. Moreover, cardiomyocyte-specific overexpression of CDC20 had no effect on the therapeutic efficacy of DOX against tumors. Conclusion Our findings indicate that CDC20 safeguards the heart against DOX-induced cardiotoxicity by modulating CCDC69 degradation without compromising the antitumor efficacy of DOX. Graphical Abstract |
| format | Article |
| id | doaj-art-853d1067861d4396bfa80e4449d9a3fe |
| institution | Kabale University |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-853d1067861d4396bfa80e4449d9a3fe2025-08-20T03:42:55ZengBMCCellular & Molecular Biology Letters1689-13922025-03-0130112310.1186/s11658-025-00708-8CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradationZhenyu Feng0Ningning Zhang1Liang Wang2Xumin Guan3Yunpeng Xie4Yun-long Xia5Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Dalian Medical UniversityDepartment of Pharmacy, Liaoyang City Central HospitalInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical UniversityInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical UniversityInstitute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical UniversityAbstract Aims Doxorubicin (DOX) is a potent anticancer drug; however, it is associated with significant cardiotoxicity. CDC20 is an E3 ubiquitin ligase that plays a role in cell cycle progression and apoptosis in various types of cancers. The involvement of CDC20 in DOX-induced cardiotoxicity (DIC) is poorly understood. Hence, this study aimed to explore the potential role of CDC20 in the development of DIC and assess whether CDC20 influences the antitumor effects of DOX. Methods and results H9C2 cells were treated with DOX, followed by transcriptomic analysis to identify differentially expressed genes. C57BL/6 mice were treated with DOX for 4 weeks after tail vein injection of CDC20 myocardial-specific knockout mice, AAV9-cTNT-(si) CDC20, or intraperitoneal injection of apcin. Cardiac function and pathological changes were evaluated by echocardiography and pathological staining, respectively. The influence of CDC20 on DOX-induced tumor inhibition was assessed in tumor-bearing mice. In vitro analysis involved treating cardiomyocytes with the Ad-CDC20 adenovirus and DOX, followed by proteomic and ubiquitination-related assays to identify potential downstream ubiquitinated CDC20 proteins. Additionally, we investigated the effect of CCDC69 on CDC20-mediated protection against DOX-induced apoptosis using CCDC69 shRNA. Transcriptome analysis revealed that DOX effectively suppressed the expression of CDC20. Cardiomyocyte-specific overexpression of CDC20 in a DOX-induced mouse model of myocardial injury effectively mitigated cardiomyocyte apoptosis, inflammation, fibrosis, and cell atrophy. Our mechanistic investigation revealed that CDC20 attenuates DOX-induced apoptosis by downregulating CCDC69 expression. Moreover, cardiomyocyte-specific overexpression of CDC20 had no effect on the therapeutic efficacy of DOX against tumors. Conclusion Our findings indicate that CDC20 safeguards the heart against DOX-induced cardiotoxicity by modulating CCDC69 degradation without compromising the antitumor efficacy of DOX. Graphical Abstracthttps://doi.org/10.1186/s11658-025-00708-8ApoptosisCDC20CCDC69DoxorubicinHeart failure |
| spellingShingle | Zhenyu Feng Ningning Zhang Liang Wang Xumin Guan Yunpeng Xie Yun-long Xia CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation Cellular & Molecular Biology Letters Apoptosis CDC20 CCDC69 Doxorubicin Heart failure |
| title | CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation |
| title_full | CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation |
| title_fullStr | CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation |
| title_full_unstemmed | CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation |
| title_short | CDC20 protects the heart from doxorubicin-induced cardiotoxicity by modulating CCDC69 degradation |
| title_sort | cdc20 protects the heart from doxorubicin induced cardiotoxicity by modulating ccdc69 degradation |
| topic | Apoptosis CDC20 CCDC69 Doxorubicin Heart failure |
| url | https://doi.org/10.1186/s11658-025-00708-8 |
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