CCNE1 stabilizes ANLN by counteracting FZR1-mediated the ubiquitination modification to promotes triple negative breast cancer cell stemness and progression.

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-05-09 DOI:10.1038/s41420-025-02518-5

Sujuan Dai, Lin Li, Guangxiu Guo, Yun Peng, Huozhong Yuan, Juntao Li

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引用次数: 0

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies. In this study, we aimed to investigate the pivotal role of cyclin E1 (CCNE1) in the onset and progression of TNBC using comprehensive bioinformatic analysis and functional validation. We found significantly elevated CCNE1 expression in TNBC tissues compared to normal, which correlated with poor prognosis. Functional assessments in vitro and in vivo demonstrated that knockdown of CCNE1 impaired the proliferative, migratory, and invasive capacities of TNBC cells, promoted apoptosis, and reduced tumorigenicity. Furthermore, CCNE1 sustains the stem-like properties of TNBC cells and fuels malignant progression through Anillin (ANLN). Mechanistically, CCNE1 interacted with ANLN and stabilized its protein levels by counteracting Fizzy-related protein 1 (FZR1)-mediated the ubiquitination modification in TNBC. Mutation of the ubiquitination site in ANLN affected CCNE1's regulatory functions but not ANLN's intrinsic properties. Taken together, these findings underscore the role of CCNE1 in promoting TNBC cell stemness and progression via competitive inhibition of FZR1-mediated ANLN ubiquitination. Consequently, targeting CCNE1 emerges as a promising therapeutic approach for breast cancer.

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CCNE1通过抑制fzr1介导的泛素化修饰来稳定ANLN，促进三阴性乳腺癌细胞的干细胞和进展。

三阴性乳腺癌（TNBC）是一种缺乏靶向治疗的侵袭性亚型。在这项研究中，我们旨在通过综合生物信息学分析和功能验证来研究细胞周期蛋白E1 （CCNE1）在TNBC发病和进展中的关键作用。我们发现，与正常组织相比，TNBC组织中CCNE1的表达显著升高，这与预后不良有关。体外和体内功能评估表明，敲低CCNE1可损害TNBC细胞的增殖、迁移和侵袭能力，促进细胞凋亡，降低致瘤性。此外，CCNE1维持TNBC细胞的干细胞样特性，并通过Anillin （ANLN）促进恶性进展。机制上，CCNE1通过抵消Fizzy-related protein 1 （FZR1）介导的TNBC泛素化修饰，与ANLN相互作用并稳定其蛋白水平。ANLN中泛素化位点的突变影响CCNE1的调控功能，但不影响ANLN的内在特性。综上所述，这些发现强调了CCNE1通过竞争性抑制fzr1介导的ANLN泛素化在促进TNBC细胞干细胞和进展中的作用。因此，靶向CCNE1是一种很有前景的乳腺癌治疗方法。

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

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.