Methyltransferase like-14 suppresses growth and metastasis of non-small-cell lung cancer by decreasing LINC02747

IF 4.5 2区 医学 Q1 ONCOLOGY
Cancer Science Pub Date : 2024-06-18 DOI:10.1111/cas.16254
Jiemin Wang, Shu Wang, Haopeng Yang, Ruixuan Wang, Kesong Shi, Yueshi Liu, Le Dou, Haiquan Yu
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引用次数: 0

Abstract

Multiple epigenetic regulatory mechanisms exert critical roles in tumor development, and understanding the interactions and impact of diverse epigenetic modifications on gene expression in cancer is crucial for the development of precision medicine. We found that methyltransferase-like 14 (METTL14) was significantly downregulated in non-small-cell lung cancer (NSCLC) tissues. Functional experiments demonstrated that overexpression of METTL14 inhibited the proliferation and migration of NSCLC cells both in vivo and in vitro, and the colorimetric m6A quantification assay also showed that knockdown of METTL14 notably reduced global m6A modification levels in NSCLC cells. By using the methylated-RNA immunoprecipitation-qPCR and dual-luciferase reporter assays, we verified that long noncoding RNA LINC02747 was a target of METTL14 and was regulated by METTL14-mediated m6A modification, and silencing LINC02747 inhibited the malignant progression of NSCLC by modulating the PI3K/Akt and CDK4/Cyclin D1 signaling pathway. Further studies revealed that overexpression of METTL14 promoted m6A methylation and accelerated the decay of LINC02747 mRNA via increased recognition of the “GAACU” binding site by YTHDC2. Additionally, histone demethylase lysine-specific histone demethylase 5B (KDM5B) mediated the demethylation of histone H3 lysine 4 tri-methylation (H3K4me3) in the METTL14 promoter region and repressed its transcription. In summary, KDM5B downregulated METTL14 expression at the transcriptional level in a H3K4me3-dependent manner, while METTL14 modulated LINC02747 expression via m6A modification. Our results demonstrate a synergy of multiple mechanisms in regulating the malignant phenotype of NSCLC, revealing the complex regulation involved in the occurrence and development of cancer.

Abstract Image

Abstract Image

甲基转移酶 like-14 通过降低 LINC02747 抑制非小细胞肺癌的生长和转移。
多种表观遗传调控机制在肿瘤发生发展过程中发挥着关键作用,了解多种表观遗传修饰对癌症基因表达的相互作用和影响对于精准医疗的发展至关重要。我们发现,在非小细胞肺癌(NSCLC)组织中,甲基转移酶样 14(METTL14)被显著下调。功能实验表明,过表达METTL14可抑制NSCLC细胞在体内和体外的增殖和迁移,比色法m6A定量检测也表明,敲除METTL14可明显降低NSCLC细胞中的全局m6A修饰水平。通过甲基化-RNA免疫沉淀-qPCR和双荧光素酶报告实验,我们验证了长非编码RNA LINC02747是METTL14的靶标,并受METTL14介导的m6A修饰调控,沉默LINC02747可通过调节PI3K/Akt和CDK4/Cyclin D1信号通路抑制NSCLC的恶性进展。进一步的研究发现,过量表达 METTL14 会促进 m6A 甲基化,并通过增加 YTHDC2 对 "GAACU "结合位点的识别,加速 LINC02747 mRNA 的衰变。此外,组蛋白去甲基化酶赖氨酸特异性组蛋白去甲基化酶5B(KDM5B)介导了METTL14启动子区域组蛋白H3赖氨酸4三甲基化(H3K4me3)的去甲基化,并抑制了其转录。总之,KDM5B通过H3K4me3依赖性方式在转录水平下调了METTL14的表达,而METTL14则通过m6A修饰调节了LINC02747的表达。我们的研究结果表明,多种机制协同调控 NSCLC 的恶性表型,揭示了癌症发生和发展过程中的复杂调控机制。
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来源期刊
Cancer Science
Cancer Science 医学-肿瘤学
自引率
3.50%
发文量
406
审稿时长
2 months
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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