Pei Lipeng, Zhu Yan, Li Wenpeng, Xu Bin, Sun Jingli
Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenhe District, Shenyang, 110016, China.
Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenhe District, Shenyang, 110016, China.
Mol Med. 2025 Feb 3;31(1):39. doi: 10.1186/s10020-025-01082-z.
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.
背景：子宫内膜癌（UCEC）是最常见的女性生殖系统恶性肿瘤之一。针对DNA损伤和细胞凋亡被认为是UCEC治疗的有效途径。雷公藤红素是一种来自卫矛科植物家族的天然抗癌产物，但其在UCEC中的作用尚未得到研究。 方法：应用UCEC细胞系Ishikawa和HEC-1-A，并使用不同浓度的雷公藤红素进行处理。将合适的无毒浓度用于后续实验。功能实验分析了细胞活力、细胞周期分布、DNA损伤、细胞凋亡以及相关蛋白的表达。我们测定了异种移植裸鼠中的肿瘤生长情况。进行生物信息学分析、蛋白质免疫共沉淀（Co-IP）、荧光素酶测定和细胞实验，以揭示雷公藤红素/KAT2B/RBPJ/MCM4在UCEC中的关系。 结果：雷公藤红素处理以剂量依赖性方式抑制细胞活力，并导致细胞周期停滞，同时伴随着CDK2和细胞周期蛋白E表达的下调以及p21的上调。雷公藤红素处理导致培养细胞中的DNA损伤和细胞凋亡，TUNEL阳性细胞数量增加、caspase-3活性以及裂解的caspase-9、裂解的PARP1和γ-H₂AX的表达增加证明了这一点。在异种移植裸鼠中，雷公藤红素也抑制肿瘤生长。此外，赖氨酸乙酰转移酶KAT2B是雷公藤红素的一个假定靶点，其表达在体外和体内均被雷公藤红素上调。UCEC中KAT2B的过表达抑制细胞增殖并增加DNA损伤和细胞凋亡。KAT2B基因敲低克服了雷公藤红素的抗增殖和促凋亡作用。此外，Co-IP证明KAT2B与转录抑制因子RBPJ结合，并增加RBPJ的乙酰化。RBPJ可以与MCM4启动子结合以抑制荧光素酶活性。进一步的功能分析表明，KAT2B在UCEC细胞增殖、DNA损伤和细胞凋亡中的功能是由MCM4介导的，并且雷公藤红素增强RBPJ乙酰化并降低MCM4表达。 结论：这些结果强调，雷公藤红素是一种有前景的UCEC抗癌药物，通过KAT2B/RBPJ/MCM4轴具有优先的抗增殖、促凋亡和DNA损伤作用，并且KAT2B是UCEC一个有前景的治疗靶点。
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