ALKBH5 and nickel-induced lung carcinogenesis

ALKBH5 和镍诱导的肺癌发生

• 批准号: 10569871
• 负责人: Hong Sun
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-10 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10569871
• 关键词: Address; Anchorage-Independent Growth; Binding Proteins; Cancer Patient; Carcinogens; Cells; Clinical; DNA Methylation; Down-Regulation; Ectopic Expression; Environmental Exposure; Environmental Impact; Enzymes; Epigenetic Process; Epithelial Cells; Event; Exhibits; Exposure to; Genes; Human; In Vitro; Incidence; Lung; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Messenger RNA; Methylation; Methyltransferase; Modification; Monitor; Nickel; Nose; Nude Mice; Occupational Exposure; Outcome; Phenotype; Play; Prognostic Marker; Proteins; RNA; RNA Splicing; RNA Stability; RNA metabolism; RNA methylation; RNA-Binding Proteins; Reporting; Research Proposals; Role; Series; Signal Transduction; Stress; Translations; Tumor Suppressor Genes; Tumorigenicity; Up-Regulation; base; bronchial epithelium; cancer cell; carcinogenesis; carcinogenicity; cell transformation; epidemiology study; epitranscriptome; histone modification; imprint; improved; insight; knock-down; lung carcinogenesis; mRNA Expression; mRNA Stability; methyl group; protein expression; response; success; therapeutic target; transcriptome; tumor; tumor xenograft

Project Summary Nickel compounds are well-established human carcinogens. Epidemiological studies have reported an increased incidence of lung and nasal cancer following long-term exposure to nickel compounds due to either environmental or occupational exposure. Growing evidence indicates that alterations of the epigenetic landscape, including DNA methylation and histone modification, are important mechanisms in nickel-induced lung carcinogenesis. However, the impact of nickel exposure on the epitranscriptome and the potential role of RNA modification in nickel carcinogenesis have never been explored. Our preliminary studies discovered that human bronchial epithelial cells exposed to nickel compounds exhibited reduced mRNA stability of maternally expressed gene 3 (MEG3), an imprinted gene that was downregulated in many types of tumors and a strong driver for nickel-induced malignant transformation. In addition, nickel upregulated m6A demethylase ALKBH5 mRNA and protein expression that coincided with MEG3 RNA destabilization, suggesting ALKBH5 may contribute to cell transformation via modulating global- or gene-specific m6A abundance. Moreover, knockdown of ALKBH5 completely abolished MEG3 degradation in nickel-exposed cells, suggesting that RNA methylation may play a role in protecting MEG3 stability. However, it is not clear how nickel upregulates ALKBH5 as well as whether increased ALKBH5 mediates nickel-induced cell transformation. Additionally, how m6A abundance modulates MEG3 RNA stability remains largely unknown. Therefore, in this application, two specific aims were proposed to address the key events in nickel-induced MEG3 destabilization. The first aim will address whether increased ALKBH5 is sufficient to induce malignant transformation in vitro. The second aim will target the potential upstream regulators and downstream effectors that mediate nickel-induced ALKBH5 expression and MEG3 destabilization. To the best of our knowledge, this is the first proposal to tackle the impact of environmental nickel exposure on the changes of m6A enzymes as well as transcriptome-wide or gene-specific m6A methylation profiles. Success of this proposal will facilitate our understanding of how nickel targets RNA modification enzymes or RNA binding proteins to initiate or promote lung tumor formation, and further identify new aspects of m6A enzymes as a prognostic biomarkers or therapeutic targets to improve clinical outcomes of lung cancer patients.

项目摘要 镍化合物是公认的人类致癌物质。流行病学研究报告了一种 长期接触镍化合物会增加肺癌和鼻癌的发病率 环境或职业暴露。越来越多的证据表明，表观遗传学的变化 景观，包括DNA甲基化和组蛋白修饰，是镍诱导的重要机制 肺癌的发生。然而，镍暴露对表位转录组学的影响及其潜在的作用 RNA修饰在镍致癌中的作用从未被探索过。我们的初步研究发现， 人支气管上皮细胞暴露于镍化合物后，母体的mRNA稳定性降低 表达基因3(MEG3)，一种印迹基因，在许多类型的肿瘤中下调，并强烈 镍诱发恶性转化的驱动因素。此外，镍还上调了M6A去甲基酶ALKBH5的表达 与MEG3 RNA失稳一致的mRNA和蛋白质表达，表明ALKBH5可能 通过调节全球或基因特异性的m6A丰度来促进细胞转化。此外，击倒 ALKBH5完全消除了镍暴露细胞中MEG3的降解，这表明RNA甲基化 可能起到保护MEG3稳定性的作用。然而，目前尚不清楚镍是如何上调ALKBH5以及 ALKBH5升高是否介导镍诱导的细胞转化。此外，M6A的丰度 调节MEG3 RNA的稳定性在很大程度上尚不清楚。因此，在此应用程序中，有两个具体目标 建议解决镍引起的MEG3不稳定的关键事件。第一个目标将解决是否 ALKBH5的增加足以在体外诱导恶性转化。第二个目标将针对 潜在的上游调节因子和下游效应因子，介导镍诱导的ALKBH5表达和 MEG3不稳定。据我们所知，这是第一个解决环境影响的提案 镍暴露对m6A酶及转录组或基因特异性m6A变化的影响 甲基化特征。这一提议的成功将有助于我们理解镍是如何靶向RNA的 修饰酶或RNA结合蛋白以启动或促进肺癌的形成，并进一步鉴定 M6A酶作为预后生物标志物或治疗靶点改善临床疗效的新方面 肺癌患者。