Role of the Epitranscriptome in Cancer

表观转录组在癌症中的作用

• 批准号: 9979795
• 负责人: Richard I. Gregory
• 金额: $ 106.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9979795
• 关键词: American; Antineoplastic Agents; Cancer Model; Clinic; Colon; Colon Adenocarcinoma; DNA Methylation; DNA Modification Methylases; Disease; Drug Targeting; Epigenetic Process; Gene Expression; Goals; Growth; Human; Lead; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Maps; Medicine; Messenger RNA; Methylation; Methyltransferase; Modification; Mus; Normal tissue morphology; Oncogenes; Oncogenic; Pathway interactions; RNA methylation; Role; Testing; Therapeutic Intervention; Work; Xenograft procedure; cancer cell; druggable target; effective therapy; epitranscriptome; high throughput screening; histone methyltransferase; histone modification; innovation; new therapeutic target; small molecule; therapeutic target; tumor

Role of the Epitranscriptome in Cancer More than 600,000 Americans will die this year from cancer. One limitation in treating this devastating disease is the lack of “druggable” targets for therapeutic intervention. Over the last thirty years much work has been done on understanding how epigenetic changes including DNA methylation, and histone modifications influence gene expression and contribute to cancer, and drugs targeting certain DNA or histone methyltransferases are used in the clinic. It is emerging that mammalian messenger RNAs (mRNAs) are also subject to various posttranscriptional modifications including methylation but the relevance of this pathway in cancer has not yet been examined. The ambitious goal of this pioneering proposal is to explore the relevance of mRNA methylation in cancer and to establish the “epitranscriptome” as a new and effective cancer therapeutic target. To accomplish this we will map the epitranscriptome in a panel of primary human lung- and colon adenocarcinomas as well as matched normal tissues, explore the mechanism and function of altered mRNA methylation in human cancer cells and mouse cancer models, and perform high-throughput screening to identify small molecules that can specifically inhibit certain mRNA methyltransferases. The molecules we identify will be tested in cancer cells and mouse xenografts for their ability to restore mRNA methylation as a means to suppress oncogene expression and cancer growth. This work promises to transform the field of cancer medicine by establishing the epitranscriptome as a novel therapeutic target and could lead to more effective treatments for lung, colon and other tumor types.

表位转录组学在肿瘤中的作用 今年将有60多万美国人死于癌症。在处理这一毁灭性事件时有一个局限性 疾病是缺乏可用于治疗干预的“可用药”靶点。在过去的三十年里，做了很多工作 已经在理解表观遗传学的变化，包括DNA甲基化和组蛋白方面做了一些工作 修饰会影响基因表达并导致癌症，而针对某些DNA或 组蛋白甲基转移酶在临床上有广泛应用。有研究表明，哺乳动物信使RNA (MRNAs)也受到包括甲基化在内的各种转录后修饰的影响，但 这一途径与癌症的相关性尚未得到检验。这个开创性的雄心勃勃的目标 建议探索mRNA甲基化与癌症的相关性，并建立“表位转录组” 作为一种新的有效的癌症治疗靶点。为了实现这一点，我们将把表位翻译组映射到 人类原发肺腺癌和结肠腺癌以及匹配的正常组织的小组，探索 人癌细胞和小鼠肿瘤模型中mRNA甲基化改变的机制和功能， 并进行高通量筛选，以确定能够特异性抑制特定mRNA的小分子 甲基转移酶。我们确定的分子将在癌细胞和小鼠移植瘤中进行测试 能够恢复mRNA甲基化作为抑制癌基因表达和癌症生长的一种手段。这 这项工作有望改变癌症医学领域的面貌，将其作为一部小说 治疗靶点，并可能导致更有效的治疗肺癌、结肠癌和其他类型的肿瘤。