Role of the Epitranscriptome in Cancer

表观转录组在癌症中的作用

• 批准号: 10450108
• 负责人: Richard I. Gregory
• 金额: $ 104.08万
• 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/10450108
• 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.

表位转录组在癌症中的作用 今年将有超过60万美国人死于癌症。治疗这种毁灭性的疾病的一个局限性是 疾病的最大问题是缺乏用于治疗干预的“可药物化”目标。在过去的三十年里， 已经完成了对表观遗传变化的理解，包括DNA甲基化和组蛋白 修饰影响基因表达并导致癌症，靶向某些DNA或 组蛋白甲基转移酶用于临床。哺乳动物的信使RNA （mRNA）也经历各种转录后修饰，包括甲基化，但甲基化的修饰是不可逆的。 该途径在癌症中的相关性尚未被研究。这一开创性的雄心勃勃的目标 一项旨在探索mRNA甲基化在癌症中的相关性并建立“表位转录组”的提案。 作为一种新的有效的癌症治疗靶点。为了实现这一目标，我们将在 一组原发性人肺腺癌和结肠腺癌以及匹配的正常组织，探索 在人类癌细胞和小鼠癌症模型中改变mRNA甲基化的机制和功能， 并进行高通量筛选，以确定可以特异性抑制某些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异种移植物中进行测试，以确定其 恢复mRNA甲基化的能力，作为抑制癌基因表达和癌症生长的手段。这 这项工作有望通过将epitranscriptome建立为一种新的癌症医学领域， 这可能会导致对肺，结肠和其他肿瘤类型的更有效的治疗。