SP1 promotes triple-negative breast cancer progression by targeting USP5.

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-05-15 DOI:10.1186/s12935-025-03802-1

Shi-Yi Wu, Zi-Mei Peng, Feng-Yi Deng, Jin-Yong Xiong, Pu-Ying Luo, Xiao-Jian Han, Zhen Zhang

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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SP1通过靶向USP5促进三阴性乳腺癌的进展。

背景：三阴性乳腺癌（TNBC）的特点是缺乏靶向治疗和预后不佳，因此有必要对TNBC发病机制的分子机制进行关键探索，并确定新的治疗靶点。虽然在多种恶性肿瘤中观察到USP5表达失调，但其在TNBC中的具体功能和机制尚不清楚。方法：采用TCGA数据库分析、免疫组化染色（IHC）、定量RT-PCR、western blotting等方法联合检测USP5、SP1在TNBC中的表达。此外，通过CCK-8实验、菌落形成实验、EDU结合实验和肿瘤异种移植实验，研究了SP1-USP5轴和USP5抑制剂periplocin在TNBC进展中的作用。此外，本研究还利用荧光素酶法、ChIP-qPCR、定量RT-PCR和western blotting法探讨了TNBC中USP5表达调控的潜在机制。为了确定USP5活性的潜在抑制因子，我们采用分子操作环境（MOE）多功能对接平台、细胞热移测定和体外USP5活性测定相结合的方法。结果：在目前的研究中，我们观察到USP5在TNBC中表达升高，并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periplocin被认为是一种很有前景的USP5抑制剂，显示出阻止TNBC进展的潜在功效。结论：我们的研究结果表明，SP1-USP5信号通路显著参与TNBC的进展，periplocin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TNBC患者的新治疗策略提供了有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.