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.

项目概要/摘要 目前缺乏有效的靶向癌症治疗反映出人们对癌症的认识存在差距 促进肿瘤发生的机制并强调需要新的治疗方法。 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。 进展已经建立了表观转录组学，详细介绍了 RNA 的调控和功能作用 修饰，作为肿瘤发生的新兴机制和潜在的治疗途径。 甲基腺苷 (m6A) 是信使 RNA (mRNA) 上最常见的修饰，在 然而，我们对 mRNA m6A 甲基化如何影响的理解。 肿瘤发生是有限的，需要进一步研究，我的建议的 F99 阶段将确定。 ALKBH1 是 Fe2+/𝛼𝛼-酮戊二酸依赖性双加氧酶 AlkB 家族的成员，在 调节砷诱导的皮肤致瘤性中的 mRNA m6A 甲基化。 受污染的饮用水中的砷是皮肤癌的主要致癌因素。 砷诱导皮肤致瘤性的机制仍然知之甚少，并且很少有治疗方法 我已经确定了 ALKBH1 通过砷诱导的皮肤肿瘤发生的靶点。 mRNA 上的 m6A 去甲基化并在转录后调节基因表达。 该提案将解决围绕砷的分子机制的关键知识空白 诱导皮肤致瘤性，并建立 ALKBH1 和/或其靶点作为砷诱导皮肤致瘤性的治疗靶点 K00 阶段将解决更广泛的问题并描述 m6A 甲基化在皮肤癌中的动态作用。 然而，恶变是一个动态的过程。 驱动恶性转化的机制仅限于未转化和未转化的静态比较 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 K00 阶段将通过使用 m6A 测序来纵向解决这一知识空白。 使用经过验证的体外转化模型来分析 m6A 依赖性表观转录组 我发现 m6A 依赖性表观转录组在整个过程中动态变化。 恶性转化，我将确定新的 m6A 依赖性靶标，这将增加我们的 了解从正常细胞转化为致瘤细胞的过程。 该提案的 F99 和 K00 阶段的成功完成将建立 m6A 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调查员并经营一个跨学科实验室 美国国立卫生研究院 (NIH) 资助的研究表观转录组学与癌症之间相互作用的工作。