Chen Cui, Yao Hanming, Jie Haiqing, Liang Zhenkang, Zhang Yuxuan, Wen Xinyun, Zhao Jinze, Xiong Huiping, Zheng Zongheng, Wu Juekun
Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat- Sen University, Sun Yat-sen University, Guangzhou, China.
Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China.
Breast Cancer Res. 2025 Jun 5;27(1):100. doi: 10.1186/s13058-025-02054-1.
Breast cancer (BRCA) remains a significant global health concern, with the need for novel therapeutic targets to improve patient outcomes. The role of the SENP family of de-SUMOylating enzymes in BRCA is not yet fully understood.
The expression and prognostic value of SENP family in BRCA were analyzed using the TCGA database. GSEA was conducted to identify correlations between SENP5 expression and cell cycle pathways. Experiments including Western blotting, RT-qPCR, CCK8 assays, colony formation assays, EdU staining, wound healing assays, and transwell assays were used to assess the impact of SENP5 knockdown on BRCA cell proliferation, migration, and invasion. Co-immunoprecipitation and fluorescence co-localization studies were employed to investigate the interaction between SENP5 and CDK1. The effects of combining SENP5 knockdown with CDK1 inhibition were evaluated in MDA-MB-231 xenograft mouse model.
SENP5 was found to be overexpressed in BRCA and associated with poor prognosis. Knockdown of SENP5 significantly inhibited BRCA cell proliferation and migration. GSEA revealed a strong correlation between SENP5 and the cell cycle, particularly the G2M checkpoint and E2F target pathways. SENP5 was shown to promote cell cycle progression by upregulating CDK1. Mechanistically, SENP5 mediates the de-SUMOylation of CDK1, reducing its degradation via the ubiquitin-proteasome pathway and increasing CDK1 expression. In vivo, the combination of SENP5 knockdown and CDK1 inhibition significantly suppressed BRCA tumor growth.
Our research identifies the SENP5/CDK1 axis as a key player in BRCA progression, highlighting its potential as a therapeutic target.
乳腺癌（BRCA）仍然是一个重大的全球健康问题，需要新的治疗靶点来改善患者预后。去SUMO化酶SENP家族在BRCA中的作用尚未完全明确。
利用TCGA数据库分析SENP家族在BRCA中的表达及预后价值。进行基因集富集分析（GSEA）以确定SENP5表达与细胞周期通路之间的相关性。采用蛋白质免疫印迹法、逆转录-定量聚合酶链反应（RT-qPCR）、细胞计数试剂盒8（CCK8）检测、集落形成实验、5-乙炔基-2'-脱氧尿苷（EdU）染色、伤口愈合实验和Transwell实验等评估敲低SENP5对BRCA细胞增殖、迁移和侵袭的影响。采用免疫共沉淀和荧光共定位研究来探究SENP5与细胞周期蛋白依赖性激酶1（CDK1）之间的相互作用。在人乳腺癌MDA-MB-231细胞系异种移植小鼠模型中评估联合敲低SENP5与抑制CDK1的效果。
发现SENP5在BRCA中高表达且与不良预后相关。敲低SENP5显著抑制BRCA细胞增殖和迁移。GSEA显示SENP5与细胞周期密切相关，尤其是G2/M期检查点和E2F靶点通路。结果表明SENP5通过上调CDK1促进细胞周期进程。机制上，SENP5介导CDK1的去SUMO化，减少其通过泛素-蛋白酶体途径的降解并增加CDK1表达。在体内，敲低SENP5与抑制CDK1联合使用可显著抑制BRCA肿瘤生长。
我们的研究确定SENP5/CDK1轴是BRCA进展中的关键因素，突出了其作为治疗靶点的潜力。
