Wu Shi-Yi, Peng Zi-Mei, Deng Feng-Yi, Xiong Jin-Yong, Luo Pu-Ying, Han Xiao-Jian, Zhang Zhen
Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, 152 Aiguo Road, Nanchang, Jiangxi, 330006, China.
Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi, China.
Cancer Cell Int. 2025 May 15;25(1):177. doi: 10.1186/s12935-025-03802-1.
Triple-negative breast cancer (TNBC) is characterized by the absence of targeted therapies and a dismal prognosis, necessitating a critical exploration of the molecular mechanisms driving TNBC pathogenesis and the identification of novel therapeutic targets. While dysregulated USP5 expression has been observed in various malignancies, its specific functions and mechanisms in TNBC remain poorly understood.
The study utilized a combination of TCGA database analysis, immunohistochemistry staining (IHC), quantitative RT-PCR, and western blotting assay to investigate the expression of USP5 and SP1 in TNBC. Furthermore, the study examined the role of the SP1-USP5 axis and the USP5 inhibitor periplocin in TNBC progression through CCK-8 assay, colony formation assay, EDU incorporation assay, and tumor xenograft experiments. Additionally, the study explored the underlying mechanisms involved in the regulation of USP5 expression in TNBC using luciferase assay, ChIP-qPCR, quantitative RT-PCR, and western blotting assay. In order to ascertain potential inhibitors of USP5 activity, a combination of the Molecular Operating Environment (MOE) multi-functional docking platform, cellular thermal shift assay, and in vitro USP5 activity assay were utilized.
In the current investigation, it was observed that the expression of USP5 was elevated in TNBC and was significantly correlated with decreased overall survival rates among patients. The upregulation of USP5 was found to be mediated by the transcription factor SP1 through its binding to the USP5 promoter, consequently facilitating the progression of TNBC. Notably, the natural compound periplocin was identified as a promising inhibitor of USP5, demonstrating potential efficacy in impeding the advancement of TNBC.
Our research findings indicate that the SP1-USP5 signaling pathway is significantly involved in the advancement of TNBC, and periplocin's ability to target USP5 presents a potential therapeutic approach for managing TNBC. These results offer valuable insights for the development of novel treatment strategies for TNBC patients.
三阴性乳腺癌（TNBC）的特点是缺乏靶向治疗且预后不佳，因此迫切需要深入探究驱动TNBC发病机制的分子机制，并确定新的治疗靶点。虽然在各种恶性肿瘤中都观察到USP5表达失调，但其在TNBC中的具体功能和机制仍知之甚少。
本研究结合TCGA数据库分析、免疫组织化学染色（IHC）、定量逆转录-聚合酶链反应（qRT-PCR）和蛋白质免疫印迹分析，研究TNBC中USP5和SP1的表达。此外，本研究通过细胞计数试剂盒-8（CCK-8）检测、集落形成实验、5-乙炔基-2'-脱氧尿苷（EDU）掺入实验和肿瘤异种移植实验，研究SP1-USP5轴和USP5抑制剂杠柳毒苷在TNBC进展中的作用。此外，本研究使用荧光素酶实验、染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）、qRT-PCR和蛋白质免疫印迹分析，探索TNBC中USP5表达调控的潜在机制。为了确定USP5活性的潜在抑制剂，本研究联合使用分子操作环境（MOE）多功能对接平台、细胞热位移实验和体外USP5活性实验。
在本研究中，观察到USP5在TNBC中表达升高，且与患者总生存率降低显著相关。发现USP5的上调是由转录因子SP1通过其与USP5启动子的结合介导的，从而促进TNBC的进展。值得注意的是，天然化合物杠柳毒苷被确定为一种有前景的USP5抑制剂，在阻碍TNBC进展方面显示出潜在疗效。
我们的研究结果表明，SP1-USP5信号通路在TNBC进展中起重要作用，杠柳毒苷靶向USP5的能力为TNBC的治疗提供了一种潜在的治疗方法。这些结果为开发针对TNBC患者的新治疗策略提供了有价值的见解。
