CCNY-mediated phosphorylation and TET2-BACH1-driven DNA demethylation activate PRC1 to augment NSCLC progression.

IF 12.8 1区医学 Q1 ONCOLOGY

Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-15 DOI:10.1186/s13046-025-03472-x

Dayu Huang, Xianglin Chu, Chunxiao Wu, Xuan Wang, Mengkun Shi, Xiaofeng Chen, Yubao Lyu, Dapeng Li, Xuyu Gu

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引用次数: 0

Abstract

Background: The protein regulator of cytokinesis 1 (PRC1) is a prognostic marker characterized by low DNA methylation in lung cancer. This study aims to examine the function of PRC1 in non-small cell lung cancer (NSCLC) cells and investigates its regulatory mechanisms.

Methods: PRC1 expression in NSCLC cells was assessed using qPCR and western blot analyses. Loss- and gain-of-function assays of PRC1 were performed in NSCLC cells to analyze its effect on cell cycle progression and growth. Genetic knockdown or pharmaceutical inhibition of cyclin Y (CCNY), tet methylcytosine dioxygenase 2 (TET2), and BTB domain and CNC homolog 1 (BACH1) was conducted to analyze their influence on PRC1 phosphorylation or transcription. Subcutaneous xenograft and orthotopic isograft tumor models were generated for in vivo verification. Tissue microarray (TMA) and bioinformatics analyses were employed to evaluate the clinical prognostic value of CCNY, TET2, and PRC1 in NSCLC.

Results: PRC1 was highly expressed in NSCLC cells. Silencing either PRC1 or CCNY, which promotes PRC1 phosphorylation, substantially reduced cell growth in vitro, impaired spindle formation, promoted G2/M phase cell cycle arrest, increased multi-nucleated cells, and weakened tumorigenic activity of cells. Moreover, TET2 was found to induce DNA demethylation of PRC1 and activate its transcription by interacting with BACH1. Inhibition of TET2, BACH1, or the PLK1-PRC1 interaction weakened the tumorigenic potential of NSCLC cells in vivo. The TMA analysis revealed increased levels of CCNY, TET2, and phosphorylated PRC1 in tumor tissues. Bioinformatics analyses suggested that these molecules were correlated with unfavorable prognosis in NSCLC patients.

Conclusion: This study demonstrates a critical oncogenic role of PRC1 in NSCLC. CCNY, which modulates PRC1 phosphorylation, and the TET2-BACH1 cascade, which modulates demethylation and transcription of PRC1, may serve as promising targets for NSCLC management.

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ccny介导的磷酸化和tet2 - bach1驱动的DNA去甲基化激活PRC1以增加NSCLC的进展。

背景：细胞分裂1蛋白调节因子（PRC1）是肺癌中以低DNA甲基化为特征的预后标志物。本研究旨在探讨PRC1在非小细胞肺癌（NSCLC）细胞中的功能，并探讨其调控机制。方法：采用qPCR和western blot检测非小细胞肺癌细胞中PRC1的表达。在非小细胞肺癌细胞中进行了PRC1的功能丧失和功能获得分析，以分析其对细胞周期进展和生长的影响。通过基因敲低或药物抑制细胞周期蛋白Y （CCNY）、tet甲基胞嘧啶双加氧酶2 （TET2）、BTB结构域和CNC同源物1 (BACH1)，分析它们对PRC1磷酸化或转录的影响。皮下异种移植和原位等移植肿瘤模型生成用于体内验证。采用组织微阵列（TMA）和生物信息学分析评估CCNY、TET2和PRC1在非小细胞肺癌中的临床预后价值。结果：PRC1在NSCLC细胞中高表达。沉默PRC1或CCNY，可促进PRC1磷酸化，显著降低体外细胞生长，破坏纺锤体形成，促进G2/M期细胞周期阻滞，增加多核细胞，减弱细胞的致瘤活性。此外，TET2通过与BACH1相互作用，诱导PRC1的DNA去甲基化并激活其转录。抑制TET2、BACH1或PLK1-PRC1相互作用可在体内减弱NSCLC细胞的致瘤潜能。TMA分析显示肿瘤组织中CCNY、TET2和磷酸化PRC1水平升高。生物信息学分析表明，这些分子与NSCLC患者的不良预后相关。结论：本研究表明PRC1在非小细胞肺癌中具有重要的致癌作用。调节PRC1磷酸化的CCNY和调节PRC1去甲基化和转录的TET2-BACH1级联可能成为NSCLC治疗的有希望的靶点。

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

Journal of Experimental & Clinical Cancer Research 医学-肿瘤学

CiteScore

18.20

自引率

1.80%

发文量

333

审稿时长

1 months

期刊介绍： The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.