RNF11 confers chemotherapy sensitivity to tumor cells by regulating the ubiquitination of KU80 and the cell cycle

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling Pub Date : 2025-08-26 DOI:10.1016/j.cellsig.2025.112088

Cheng Wei , Xiaojun Li , Zhen Wei , Boxiong Kang , Jie Fu , Xingang Wang , Minxue Chen , Xinyuan Zhou , Qiuya Wei , Chen Wang

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引用次数: 0

Abstract

Background

Ring finger protein 11 (RNF11) is integral to cell signal transduction and transcription factor regulation and is strongly connected to the beginning and progression of malignant tumors. However, the core mechanisms of RNF11 remain unknown to date. This study highlights the significant function of RNF11 in the DNA damage response.

Methods

After the CRISPR-Cas9 gene knockout of RNF11, HCT116 cells were transfected, and cell viability assays were performed to evaluate the response of tumor cells to the chemotherapy drugs after RNF11 deletion. The interaction of RNF11 with its binding proteins and its ubiquitination mechanism, along with the recruitment of KU80 to chromatin, were subsequently evaluated. RNF11 was revealed to participate in the regulation of the cell cycle and apoptosis. An HCT116 xenograft tumor model was used to validate the in vivo sensitivity of tumors to 5-FU, revealing that RNF11 is essential for regulating the responsiveness of tumor cells to chemotherapy.

Results

RNF11 modulates KU80 expression and participates in cell cycle regulation. The elimination of RNF11 results in the accumulation of KU80 at the DNA damage sites, induces G1 phase cell cycle arrest, and increases sensitivity to the chemotherapy drugs. Mechanistically, RNF11 regulates KU80 expression through a direct interaction and facilitates its ubiquitination while modulating apoptosis and the cell cycle, thereby participating in the cellular damage response. Furthermore, high RNF11 expression is associated with poor prognosis in patients with cancer, while RNF11 deletion impedes tumor progression and enhances the sensitivity of the xenografts to 5-FU treatment. These findings demonstrate that RNF11 is involved in the clinical tumor treatment processes and could be a target for cancer treatment.

Conclusion

RNF11 binds with KU80, facilitates its ubiquitination, supports DNA damage repair, preserves genomic stability, and enhances the chemotherapy response in tumor cells.

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RNF11通过调节KU80的泛素化和细胞周期，赋予肿瘤细胞化疗敏感性。

背景：环指蛋白11 （Ring finger protein 11, RNF11）是细胞信号转导和转录因子调控的重要组成部分，与恶性肿瘤的发生和发展密切相关。然而，RNF11的核心机制至今仍不清楚。本研究强调了RNF11在DNA损伤应答中的重要功能。方法：CRISPR-Cas9基因敲除RNF11后，转染HCT116细胞，进行细胞活力测定，评价RNF11缺失后肿瘤细胞对化疗药物的反应。随后评估了RNF11与其结合蛋白的相互作用及其泛素化机制，以及KU80向染色质的募集。RNF11参与细胞周期和凋亡的调控。利用HCT116异种移植肿瘤模型验证肿瘤对5-FU的体内敏感性，揭示RNF11在调节肿瘤细胞对化疗的反应性中至关重要。结果：RNF11可调节KU80的表达，参与细胞周期调控。RNF11的消除导致KU80在DNA损伤位点的积累，诱导G1期细胞周期阻滞，并增加对化疗药物的敏感性。机制上，RNF11通过直接相互作用调控KU80的表达，促进KU80泛素化，同时调节细胞凋亡和细胞周期，从而参与细胞损伤应答。此外，RNF11高表达与癌症患者预后不良相关，而RNF11缺失会阻碍肿瘤进展并增强异种移植物对5-FU治疗的敏感性。这些发现表明RNF11参与了临床肿瘤治疗过程，可能成为癌症治疗的靶点。结论：RNF11与KU80结合，促进KU80泛素化，支持DNA损伤修复，保持基因组稳定性，增强肿瘤细胞化疗反应。

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

Cellular signalling 生物-细胞生物学

CiteScore

8.40

自引率

0.00%

发文量

250

审稿时长

27 days

期刊介绍： Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.