NSUN4 介导的 circERI3 m5C 修饰通过改变线粒体能量代谢促进肺癌发展。

IF 9.1 1区 医学 Q1 ONCOLOGY Cancer letters Pub Date : 2024-09-26 DOI:10.1016/j.canlet.2024.217266
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引用次数: 0

摘要

作为一种非常重要的甲基化修饰,5-甲基腺苷(m5C)修饰可通过调节 RNA 的转录、结构和稳定性对其产生深远影响。随着高通量技术的不断发展,差异表达的环状 RNA(circRNA)被越来越多地发现,circRNA 在肿瘤发生和发展中发挥着独特的作用。然而,circRNAs m5C修饰的调控机制尚未被揭示。本研究通过对circRNAs进行差异表达谱分析,初步发现了在肺癌组织中高表达且与肺癌临床进展显著相关的circERI3。结合m5C芯片分析发现,circERI3含有m5C修饰,而NSUN4介导的circERI3的m5C修饰可增加其核输出。阐明了circERI3在体外和体内促进肺癌进展的重要功能。此外,我们还阐明了circERI3靶向DNA结合蛋白1(DDB1),调控其泛素化,增强其稳定性,进而通过DDB1促进过氧化物酶体增殖激活受体γ辅激活子1α(PGC-1α)转录,影响线粒体功能和能量代谢,最终促进肺癌发展的新机制。该研究不仅从甲基化角度揭示了circERI3在肺癌组织中异常分布的原因,阐明了circERI3在肺癌进展中的重要作用,而且描述了circERI3通过线粒体能量代谢促进肺癌发展的新机制,为肺癌中circRNA的研究提供了新的思路。
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NSUN4-mediated m5C modification of circERI3 promotes lung cancer development by altering mitochondrial energy metabolism
As a highly important methylation modification, the 5-methyladenosine (m5C) modification can profoundly affect RNAs by regulating their transcription, structure and stability. With the continuous development of high-throughput technology, differentially expressed circular RNAs (circRNAs) have been increasingly discovered, and circRNAs play unique roles in tumorigenesis and development. However, the regulatory mechanism of the m5C modification of circRNAs has not yet been revealed. In this study, circERI3, which is highly expressed in lung cancer tissue and significantly correlated with the clinical progression of lung cancer, was initially identified through differential expression profiling of circRNAs. A combined m5C microarray analysis revealed that circERI3 contains the m5C modification and that the NSUN4-mediated m5C modification of circERI3 can increase its nuclear export. The important function of circERI3 in promoting lung cancer progression in vitro and in vivo was clarified. Moreover, we elucidated the novel mechanism by which circERI3 targets DNA binding protein 1 (DDB1), regulates its ubiquitination, enhances its stability, and in turn promotes the transcription of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) through DDB1 to affect mitochondrial function and energy metabolism, which ultimately promotes the development of lung cancer. This study not only revealed the reasons for the abnormal distribution of circERI3 in lung cancer tissues from the perspective of methylation and clarified the important role of circERI3 in lung cancer progression but also described a novel mechanism by which circERI3 promotes lung cancer development through mitochondrial energy metabolism, providing new insights for the study of circRNAs in lung cancer.
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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