Elucidating the role of mRNA m6A methylation in tumorigenesis

阐明 mRNA m6A 甲基化在肿瘤发生中的作用

• 批准号: 10744553
• 负责人: Emma Anne Wilkinson
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744553
• 关键词: Arsenic; Biology; Carcinogen exposure; Carcinoma; Cause of Death; Cells; Chemicals; Chronic; Data; Development; Dioxygenases; Disease; Exposure to; Family; Funding; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic; Goals; In Vitro; Investigation; Knowledge; Longitudinal Studies; Lung; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Methylation; Modeling; Modification; Molecular; Normal Cell; Pathogenesis; Phase; Postdoctoral Fellow; Primary carcinoma of the liver cells; Process; RNA; RNA immunoprecipitation sequencing; RNA metabolism; Regulation; Research; Research Personnel; Research Project Grants; Role; Running; Skin; Skin Cancer; Testing; Therapeutic; Time; Transcript; Translating; Tumorigenicity; United States National Institutes of Health; Work; arsenic carcinogenesis; cancer biomarkers; cancer therapy; cancer type; carcinogenicity; career; cell transformation; cell type; contaminated drinking water; demethylation; druggable target; epitranscriptome; epitranscriptomics; in vitro Model; in vivo; insight; keratinocyte; knock-down; member; mortality; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; posttranscriptional; potential biomarker; targeted biomarker; targeted cancer therapy; targeted treatment; therapeutic biomarker; therapeutic target; transcriptome; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT The current lack of effective, targeted cancer therapies reflects a gap in knowledge surrounding the mechanisms that promote tumorigenesis and emphasizes the need for new therapeutic approaches. For decades, genetic drivers were thought to be the sole mechanism that promote tumorigenesis. Recent advances have established epitranscriptomics, which details the regulatory and functional roles of RNA modifications, as an emerging mechanism of tumorigenesis and potential therapeutic avenue. N6- methyladenosine (m6A) is the most prevalent modification on messenger RNA (mRNA) and serves key roles in gene regulation and expression. However, our understanding of how mRNA m6A methylation contributes to tumorigenesis is limited and warrants further investigation. The F99 phase of my proposal will determine the novel role of ALKBH1, a member of the AlkB family of Fe2+/𝛼𝛼-ketoglutarate-dependent dioxygenases, in regulating mRNA m6A methylation in arsenic-induced skin tumorigenicity. Chronic exposure to inorganic arsenic through contaminated drinking water is a major carcinogenic driver of skin cancer. However, the mechanisms that underlie arsenic-induced skin tumorigenicity remain poorly understood and few therapeutic targets have been identified. I hypothesize that ALKBH1 promotes arsenic-induced skin tumorigenesis by demethylating m6A on mRNA and regulating gene expression post-transcriptionally. The F99 phase of this proposal will address critical gaps in knowledge surrounding the molecular mechanisms that underlie arsenic- induced skin tumorigenicity and establish ALKBH1 and/or its targets as therapeutic targets for arsenic-induced skin cancer. The K00 phase will address a broader question and profile the dynamic role of m6A methylation in malignant transformation. Malignant transformation is a dynamic process. However, our understanding of the mechanisms that drive malignant transformation is limited to static comparisons across non-transformed and transformed cells and the transitional states that mediate the transformation between these cell types remain uncharacterized. The K00 phase will address this gap in knowledge by using m6A-sequencing to longitudinally profile the m6A-dependent epitranscriptome using validated models of in vitro transformation across a panel of carcinomas. I hypothesize that the m6A-dependent epitranscriptome changes dynamically throughout malignant transformation and that I will identify novel m6A-dependent targets that will increase our understanding of the processes that underlie the transformation from a normal cell to a tumorigenic cell. Successful completion of the F99 and K00 phases of this proposal will establish novel mechanisms of m6A regulation and function and identify new therapeutic targets and potential biomarkers of cancer development. My ultimate career goal is to become an independent investigator and run an interdisciplinary lab conducting NIH-funded work that investigates the interplay between epitranscriptomics and cancer.

项目摘要/摘要 目前缺乏有效的靶向癌症疗法反映了围绕癌症治疗的知识差距。 促进肿瘤发生的机制，并强调需要新的治疗方法。为 几十年来，遗传驱动因素被认为是促进肿瘤发生的唯一机制。最近 随着研究的进展，已经建立了表观转录组学，它详细描述了RNA的调节和功能作用 修饰作为一种新的肿瘤发生机制和潜在的治疗途径。N6- 甲基腺苷（m6 A）是信使RNA（mRNA）上最普遍的修饰，并且在以下方面起关键作用： 基因调控和表达。然而，我们对mRNA m6 A甲基化如何有助于 肿瘤发生是有限的，需要进一步研究。我的建议的F99阶段将决定 ALKBH 1是Fe 2 +/β-酮戊二酸依赖性双加氧酶AlkB家族的成员， 调节砷诱导的皮肤致瘤性中mRNA m6 A甲基化。长期接触无机物 通过受污染的饮用水摄入的砷是导致皮肤癌的主要致癌因素。但 砷诱导皮肤致瘤性的机制仍然知之甚少， 目标已经确定。我推测ALKBH 1通过以下途径促进砷诱导的皮肤肿瘤发生： 在mRNA上使m6 A去甲基化并在转录后调节基因表达。F99阶段 该提案将解决围绕砷的分子机制的关键知识空白， 诱导的皮肤致瘤性，并建立ALKBH 1和/或其靶点作为砷诱导的皮肤致瘤性的治疗靶点。 皮肤癌K 00阶段将解决一个更广泛的问题，并分析m6 A甲基化在 恶性转化恶性转化是一个动态的过程。然而，我们对 导致恶性转化的机制仅限于对未转化和未转化的细胞进行静态比较 转化的细胞和介导这些细胞类型之间转化的过渡状态仍然存在 没有特征的K 00阶段将通过使用m6 A测序纵向 使用经验证的体外转化模型，在一组 癌我假设m6 A依赖的表转录组在整个过程中动态变化， 恶性转化，我将确定新的m6 A依赖性靶点，这将增加我们的 理解从正常细胞到致瘤细胞转化的过程。 该提案的F99和K 00阶段的成功完成将建立m6 A的新机制。 调节和功能，并确定新的治疗靶点和癌症发展的潜在生物标志物。 我的最终职业目标是成为一名独立的调查员，并运行一个跨学科的实验室， NIH资助的研究epitranscriptomics和癌症之间相互作用的工作。