UHRF1 通过促进 FDX1 启动子甲基化抑制肺腺癌中的铜死亡
UHRF1 inhibits cuproptosis in lung adenocarcinoma via promoting FDX1 promoter methylation.
作者
作者单位
- Department of Thoracic Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, No.6 Taoyuan Road, Qingxiu District, Nanning, Guangxi Zhuang Autonomous Region, 530021, China.
- Graduate School, Guangxi Medical University, Nanning, Guangxi, 530021, China.
- College of Clinical Medicine, Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China.
- Department of Thoracic Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, No.6 Taoyuan Road, Qingxiu District, Nanning, Guangxi Zhuang Autonomous Region, 530021, China. jwyan@gxams.org.cn.
- Department of Thoracic Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, No.6 Taoyuan Road, Qingxiu District, Nanning, Guangxi Zhuang Autonomous Region, 530021, China. yfzhou@gxams.org.cn.
摘要
中文
UHRF1 是参与 DNA 甲基化调控的关键表观遗传因子，在多种肿瘤的发生中发挥作用；然而其在肺腺癌（LUAD）进展中的具体机制尚不明确。本研究旨在阐明 UHRF1 在 LUAD 中的调控作用，重点关注其对铜死亡（cuproptosis）的影响。利用 TCGA-LUAD 数据集分析 UHRF1 表达及其与患者预后的相关性。通过 qPCR 和 Western blot 验证 LUAD 细胞系中 UHRF1 和 FDX1 的表达水平。采用基因集富集分析（GSEA）探索 UHRF1 相关通路。通过 CCK-8 实验、代谢物检测和凋亡分析评估 UHRF1 对铜死亡的影响。机制方面，通过染色质免疫共沉淀（ChIP）和甲基化特异性 PCR（MSP）检测 FDX1 启动子的结合和甲基化状态。最后通过异种移植小鼠模型在体内验证 UHRF1 的致癌作用。临床分析显示，LUAD 组织中 UHRF1 表达升高与不良预后显著相关。在细胞水平，UHRF1 过表达下调 FDX1 表达并抑制 DLAT 寡聚化。功能富集分析表明 UHRF1 参与代谢重编程；具体而言，其过表达可增强糖酵解同时抑制铜死亡。机制研究表明 UHRF1 直接结合 FDX1 启动子，诱导其高甲基化及随后的转录沉默。挽救实验证实，恢复 FDX1 表达可逆转 UHRF1 对铜死亡的抑制作用。在体内，敲减 UHRF1 抑制肿瘤生长并促进细胞死亡，而同时敲减 FDX1 则削弱这些抑瘤效应。UHRF1 通过 DNA 甲基化负调控 FDX1 表达，从而抑制铜死亡并驱动 LUAD 进展。这些发现阐明了 LUAD 中一种新的表观遗传机制，并提示 UHRF1/FDX1 轴可能成为潜在的治疗靶点。
English
UHRF1 is a key epigenetic regulator implicated in the tumorigenesis of various cancers through DNA methylation; however, its specific mechanisms in the progression of lung adenocarcinoma (LUAD) remain poorly understood. This study aims to elucidate the regulatory role of UHRF1 in LUAD, focusing on its impact on cuproptosis. UHRF1 expression and its correlation with patient prognosis were analyzed using the TCGA-LUAD dataset. Expression levels of UHRF1 and FDX1 in LUAD cell lines were verified via qPCR and Western blot. Gene Set Enrichment Analysis (GSEA) was employed to explore UHRF1-associated pathways. The impact of UHRF1 on cuproptosis was assessed using CCK-8 assays, metabolite detection, and apoptosis analysis. Mechanistically, Chromatin Immunoprecipitation (ChIP) and Methylation-Specific PCR (MSP) were performed to investigate the binding and methylation status of the FDX1 promoter. Finally, the oncogenic role of UHRF1 was validated in vivo using a xenograft mouse model. Clinical analysis revealed that elevated UHRF1 expression in LUAD tissues is significantly associated with poor prognosis. At the cellular level, UHRF1 overexpression downregulated FDX1 expression and inhibited DLAT oligomerization. Functional enrichment analysis indicated that UHRF1 is involved in metabolic reprogramming; specifically, its overexpression enhanced glycolysis while suppressing cuproptosis. Mechanistic studies demonstrated that UHRF1 binds directly to the FDX1 promoter, inducing hypermethylation and subsequent transcriptional silencing. Rescue experiments confirmed that restoring FDX1 expression reverses the cuproptosis-suppressive effects of UHRF1. In vivo, UHRF1 knockdown retarded tumor growth and promoted cell death, whereas concurrent FDX1 knockdown attenuated these tumor-suppressive effects. UHRF1 negatively regulates FDX1 expression through DNA methylation, thereby inhibiting cuproptosis and driving LUAD progression. These findings clarify a novel epigenetic mechanism underlying LUAD and highlight the UHRF1/FDX1 axis as a potential therapeutic target.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 5.7
- 新锐分区
- 2区