Decoding AMPK-dependent regulation of DNA methylation in lung cancer

解码肺癌中 DNA 甲基化的 AMPK 依赖性调节

基本信息

  • 批准号:
    10537799
  • 负责人:
  • 金额:
    $ 6.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-05-19 至 2025-06-18
  • 项目状态:
    未结题

项目摘要

Project Summary Lung cancer is the leading cause of cancer-related mortality worldwide. Lung tumors driven by mutant KRAS are among the most aggressive and refractory to treatment, due in part by KRAS-driven metabolic reprogramming. Efforts to better understand the pathways regulating metabolic adaptations in oncogenic KRAS- driven tumors will provide insight into lung cancer progression and identify vulnerabilities that could be therapeutically targeted to improve patient survival. The Shaw lab recently showed the requirement of AMP- activated protein kinase (AMPK) to promote the growth of oncogenic KRAS-driven non-small-cell lung cancer (NSCLC). AMPK is a master regulator of cellular and organismal metabolism that acts as a sensor of cellular energy by altering metabolism when energy levels are low. While the Shaw lab and others have demonstrated that AMPK signaling provides cancer cells with flexibility to adapt to metabolic stresses, the epigenetic mechanisms by which AMPK promotes metabolic alterations and lung tumor growth remain poorly understood. Preliminary studies identified a de novo DNA methyltransferase as a novel substrate of AMPK. DNA methylation is involved in many normal cellular processes and is abnormally distributed in cancer cells, contributing to some of their aggressive characteristics. This proposal addresses the consequences of AMPK-dependent regulation of the de novo DNA methyltransferase on DNA methylation, metabolic programs, and lung tumor growth. First, this work aims to define the methylation profile controlled by the AMPK-dependent phosphorylated form of the de novo DNA methyltransferase using whole-genome bisulfite sequencing, CUT&TAG, and RNA sequencing assays. Tumorigenicity and Seahorse real-time cell metabolic analyses will determine whether this regulation disrupts DNA methylation patterns in a manner that generates tumor-promoting epigenetic lesions and metabolic alterations. Additionally, the generation of autochthonous KRAS-driven NSCLC mouse lines expressing constitutive knock-in of the de novo DNA methyltransferase with a serine-to-alanine mutation at the putative phosphor-acceptor-serine will enable testing whether regulation of the de novo DNA methyltransferase impacts tumor initiation, growth, and metastasis. This work addresses a fundamental relationship between two hallmarks of cancer and if successful would lead to the mechanistic connection between metabolic stresses tumor cells face and how they may trigger sustained DNA methylation changes.
项目摘要 肺癌是全球癌症相关死亡的主要原因。突变型KRAS驱动的肺肿瘤 是最具侵略性和难治性的治疗,部分原因是KRAS驱动的代谢 重新编程努力更好地了解调节致癌KRAS代谢适应的途径- 驱动的肿瘤将提供对肺癌进展的深入了解,并确定可能 治疗靶向以提高患者存活率。肖实验室最近展示了AMP的需求- 活化蛋白激酶(AMPK)促进致癌KRAS驱动的非小细胞肺癌的生长 (NSCLC)。AMPK是细胞和生物体代谢的主要调节剂,其充当细胞代谢的传感器。 当能量水平低时,通过改变新陈代谢来获得能量。虽然肖实验室和其他机构已经证明 AMPK信号为癌细胞提供了适应代谢压力的灵活性,表观遗传学 AMPK促进代谢改变和肺肿瘤生长的机制仍然知之甚少。 初步研究发现,一种新的DNA甲基转移酶是AMPK的新底物。DNA甲基化 参与许多正常的细胞过程,并在癌细胞中异常分布,导致一些 他们的侵略性特征。该提案解决了AMPK依赖性调节的后果 从头DNA甲基转移酶对DNA甲基化、代谢程序和肺肿瘤生长的影响。第一、 这项工作旨在确定由AMPK依赖的磷酸化形式控制的甲基化谱, 使用全基因组亚硫酸氢盐测序、CUT&TAG和RNA测序的从头DNA甲基转移酶 分析。致瘤性和海马实时细胞代谢分析将确定这种调节是否 破坏DNA甲基化模式的方式,产生肿瘤促进表观遗传病变和代谢 改变。此外,表达KRAS的本地KRAS驱动的NSCLC小鼠系的产生, 在假定的DNA甲基转移酶基因组中, 磷酸受体丝氨酸将能够测试从头DNA甲基转移酶的调节是否影响 肿瘤起始、生长和转移。这项工作解决了两个标志之间的基本关系 如果成功的话,将导致代谢应激肿瘤细胞之间的机械联系, 以及它们如何引发持续的DNA甲基化变化。

项目成果

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