The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma.

IF 29.7 1区 医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-11-01 DOI:10.1158/2159-8290.CD-23-1212
Shiyan Wang, Yong Zeng, Lin Zhu, Min Zhang, Lei Zhou, Weixiong Yang, Weishan Luo, Lina Wang, Yanming Liu, Helen Zhu, Xin Xu, Peiran Su, Xinyue Zhang, Musaddeque Ahmed, Wei Chen, Moliang Chen, Sujun Chen, Mykhaylo Slobodyanyuk, Zhongpeng Xie, Jiansheng Guan, Wen Zhang, Aafaque Ahmad Khan, Shingo Sakashita, Ni Liu, Nhu-An Pham, Paul C Boutros, Zunfu Ke, Michael F Moran, Zongwei Cai, Chao Cheng, Jun Yu, Ming S Tsao, Housheng H He
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Abstract

Comprehensive N6-methyladenosine (m6A) epitranscriptomic profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 nonneoplastic lung tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptomic, proteomic, and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with nonneoplastic lung tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hypermethylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics by interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small-molecule inhibitor markedly diminished both EML4 m6A and protein abundance and efficiently suppressed lung metastases in vivo. Significance: Our study reveals a dynamic and functional epitranscriptomic landscape in LUAD, offering a valuable resource for further research in the field. We identified EML4 hypermethylation as a key driver of tumor metastasis, highlighting a novel therapeutic strategy of targeting EML4 to prevent LUAD metastasis.

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肺腺癌的 N6-甲基腺苷表转录组图谱
对原发性肿瘤进行全面的 m6A 表转录组分析在很大程度上仍是未知的。在这里,我们分析了 10 个非肿瘤性肺(NL)组织和 51 个肺腺癌(LUAD)肿瘤的 m6A 表转录组,整合了相应的转录组、蛋白质组和大量临床注释。我们发现了通过 m6A 修饰与疾病进展密切相关的基因簇和基因。与 NL 组织相比,我们发现肿瘤中有 430 个转录本发生低甲基化,222 个发生高甲基化。m6A修饰促进了EML4的翻译,导致其在原发性肿瘤中广泛过表达。在功能上,EML4通过与ARPC1A相互作用来调节细胞骨架动力学,从而增强纤毛形成、细胞运动、局部侵袭和转移。在临床上,高EML4蛋白丰度与转移特征相关。METTL3小分子抑制剂可显著降低EML4 m6A和蛋白丰度,并有效抑制体内肺转移。
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
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
期刊最新文献
Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection. The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. Single-Cell View of Tumor Microenvironment Gradients in Pleural Mesothelioma. A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer. Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.
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