Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription
Abstract Background Uterine corpus endometrial carcinoma (UCEC) is one of the most frequent female genital malignant tumors. Targeting DNA damage and cell apoptosis are regarded as effective ways for UCEC therapy. Celastrol is a natural anti-cancer product from the Celastraceae plant family, while i...
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BMC
2025-02-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01082-z |
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| author | Lipeng Pei Yan Zhu Wenpeng Li Bin Xu Jingli Sun |
| author_facet | Lipeng Pei Yan Zhu Wenpeng Li Bin Xu Jingli Sun |
| author_sort | Lipeng Pei |
| collection | DOAJ |
| description | Abstract Background Uterine corpus endometrial carcinoma (UCEC) is one of the most frequent female genital malignant tumors. Targeting DNA damage and cell apoptosis are regarded as effective ways for UCEC therapy. Celastrol is a natural anti-cancer product from the Celastraceae plant family, while its role in UCEC has not been investigated. Methods UCEC cell lines Ishikawa and HEC-1-A were applied and treated with different concentrations of Celastrol. The appropriate and nontoxic concentrations were used for the subsequent experiments. Functional experiments analyzed the cell viability, cell cycle distribution, DNA damage, apoptosis and the expression of related proteins. We determined tumor growth in xenograft nude mice. Bioinformatic analysis, protein coimmunoprecipitation (Co-IP), luciferase assay, cell experiments were performed to reveal the relationship of Celastrol/KAT2B/RBPJ/MCM4 in UCEC. Results Treatment of Celastrol inhibited cell viability in a dose-dependent manner, and caused cell cycle arrest, accompanied by the downregulation of CDK2 and cyclin E expression and the upregulation of p21. Celastrol treatment resulted DNA damage and apoptosis in cultured cells, as demonstrated by increased number of TUNEL-positive cells, activity of caspase-3 and expression of cleaved-caspase-9, cleaved PARP1 and γ-H2AX. In xenograft nude mice, Celastrol also repressed tumor growth. Furthermore, lysine acetyltransferase KAT2B was a putative target of Celastrol, and its expression was upregulated by Celastrol in vitro and in vivo. Overexpression of KAT2B in UCEC inhibited cell proliferation and increased DNA damage and apoptosis. KAT2B knockdown overcame the anti-proliferative and pro-apoptotic roles of Celastrol. Moreover, Co-IP demonstrated that KAT2B bound to RBPJ, a transcriptional repressor, and increased the acetylation of RBPJ. RBPJ could bind to the MCM4 promoter to suppress the luciferase activity. Further functional analysis revealed that the functions of KAT2B in UCEC cell proliferation, DNA damage and apoptosis were mediated by MCM4, and Celastrol enhanced RBPJ acetylation and reduced MCM4 expression. Conclusions These results underscore that Celastrol is a promising anti-cancer agent in UCEC with preferential anti-proliferative, pro-apoptotic and DNA damage effects through the KAT2B/RBPJ/MCM4 axis, and KAT2B is a promising therapeutic target for UCEC. Graphical abstract |
| format | Article |
| id | doaj-art-aa43ffd287444055a0574b52b5e7555f |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Molecular Medicine |
| spelling | doaj-art-aa43ffd287444055a0574b52b5e7555f2025-02-09T12:42:07ZengBMCMolecular Medicine1528-36582025-02-0131111510.1186/s10020-025-01082-zCelastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcriptionLipeng Pei0Yan Zhu1Wenpeng Li2Bin Xu3Jingli Sun4Department of Obstetrics and Gynecology, General Hospital of Northern Theater CommandDepartment of Cardiovascular Surgery, General Hospital of Northern Theater CommandDepartment of Obstetrics and Gynecology, General Hospital of Northern Theater CommandDepartment of Obstetrics and Gynecology, General Hospital of Northern Theater CommandDepartment of Obstetrics and Gynecology, General Hospital of Northern Theater CommandAbstract Background Uterine corpus endometrial carcinoma (UCEC) is one of the most frequent female genital malignant tumors. Targeting DNA damage and cell apoptosis are regarded as effective ways for UCEC therapy. Celastrol is a natural anti-cancer product from the Celastraceae plant family, while its role in UCEC has not been investigated. Methods UCEC cell lines Ishikawa and HEC-1-A were applied and treated with different concentrations of Celastrol. The appropriate and nontoxic concentrations were used for the subsequent experiments. Functional experiments analyzed the cell viability, cell cycle distribution, DNA damage, apoptosis and the expression of related proteins. We determined tumor growth in xenograft nude mice. Bioinformatic analysis, protein coimmunoprecipitation (Co-IP), luciferase assay, cell experiments were performed to reveal the relationship of Celastrol/KAT2B/RBPJ/MCM4 in UCEC. Results Treatment of Celastrol inhibited cell viability in a dose-dependent manner, and caused cell cycle arrest, accompanied by the downregulation of CDK2 and cyclin E expression and the upregulation of p21. Celastrol treatment resulted DNA damage and apoptosis in cultured cells, as demonstrated by increased number of TUNEL-positive cells, activity of caspase-3 and expression of cleaved-caspase-9, cleaved PARP1 and γ-H2AX. In xenograft nude mice, Celastrol also repressed tumor growth. Furthermore, lysine acetyltransferase KAT2B was a putative target of Celastrol, and its expression was upregulated by Celastrol in vitro and in vivo. Overexpression of KAT2B in UCEC inhibited cell proliferation and increased DNA damage and apoptosis. KAT2B knockdown overcame the anti-proliferative and pro-apoptotic roles of Celastrol. Moreover, Co-IP demonstrated that KAT2B bound to RBPJ, a transcriptional repressor, and increased the acetylation of RBPJ. RBPJ could bind to the MCM4 promoter to suppress the luciferase activity. Further functional analysis revealed that the functions of KAT2B in UCEC cell proliferation, DNA damage and apoptosis were mediated by MCM4, and Celastrol enhanced RBPJ acetylation and reduced MCM4 expression. Conclusions These results underscore that Celastrol is a promising anti-cancer agent in UCEC with preferential anti-proliferative, pro-apoptotic and DNA damage effects through the KAT2B/RBPJ/MCM4 axis, and KAT2B is a promising therapeutic target for UCEC. Graphical abstracthttps://doi.org/10.1186/s10020-025-01082-zUterine corpus endometrial carcinomaCelastrolKAT2BAcetylationDNA damageApoptosis |
| spellingShingle | Lipeng Pei Yan Zhu Wenpeng Li Bin Xu Jingli Sun Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription Molecular Medicine Uterine corpus endometrial carcinoma Celastrol KAT2B Acetylation DNA damage Apoptosis |
| title | Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription |
| title_full | Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription |
| title_fullStr | Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription |
| title_full_unstemmed | Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription |
| title_short | Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription |
| title_sort | celastrol promotes dna damage and apoptosis in uterine corpus endometrial carcinoma via promotion of kat2b mediated rbpj acetylation and repression of mcm4 transcription |
| topic | Uterine corpus endometrial carcinoma Celastrol KAT2B Acetylation DNA damage Apoptosis |
| url | https://doi.org/10.1186/s10020-025-01082-z |
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