Epigenetic-mediated positive feedback loop facilitates the progression of lung adenocarcinoma

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-08-26 DOI:10.1016/j.isci.2025.113339

Yihang Cheng , Yifeng Luo , Tingting Hu , Qiaoling Ren , Li Xu , Tuo Yi , Yuan Tan , Wei Li , Xuxin Wang , Yaoxiang Sun , Mingzhi Chen , Zhonghua Shen , Bin Zhang , Youhuang Bai , Yue Tao , Zhihong Cao , Deqiang Sun

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引用次数: 0

Abstract

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. We performed multi-omics approaches on LUAD samples spanning different stages, establishing a detailed epigenetic landscape. We identified 1,416 regions characterized by hypo-DNA methylation and hyperchromatin accessibility associated with high mortality and recurrence rates, serving as a biomarker panel for LUAD staging and diagnosis (AUC of 0.89 and 0.87 for two-class and multi-class models). Epigenetics-related transcription factors, especially the AP-1 family, were observed at these loci, and transcriptomic profiling indicated persistent activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Hypomethylation and hyperaccessibility of AP-1 binding sites enhance EGFR and FGFBP1 expression, activating the MAPK pathway. This reveals an epigenetic-mediated positive feedback loop, MAPK→AP-1/Epigenetic Modifications→EGFR/FGFBP1→MAPK, in LUAD, highlighting the complex interplay between epigenetic modifications and LUAD progression, offering potential detection and treatment targets. These findings define a high-resolution, multi-stage epigenetic landscape of LUAD, providing a resource for biomarker discovery and mechanistic insight.

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表观遗传介导的正反馈环促进肺腺癌的进展

肺腺癌（LUAD）仍然是癌症相关死亡的主要原因。我们对跨越不同阶段的LUAD样本进行了多组学方法，建立了详细的表观遗传景观。我们确定了1,416个以低dna甲基化和高染色质可及性为特征的区域，这些区域与高死亡率和复发率相关，可作为LUAD分期和诊断的生物标志物面板（两级和多级模型的AUC分别为0.89和0.87）。在这些位点上观察到表观遗传学相关的转录因子，特别是AP-1家族，转录组学分析表明有丝分裂原活化蛋白激酶（MAPK）信号通路持续激活。AP-1结合位点的低甲基化和高可及性增强了EGFR和FGFBP1的表达，激活了MAPK通路。这揭示了LUAD中表观遗传介导的正反馈回路，MAPK→AP-1/表观遗传修饰→EGFR/FGFBP1→MAPK，突出了表观遗传修饰与LUAD进展之间的复杂相互作用，为LUAD的检测和治疗提供了潜在的靶点。这些发现定义了LUAD的高分辨率，多阶段表观遗传景观，为生物标志物的发现和机制洞察提供了资源。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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