权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma

确定 SETD2 失活对肺腺癌的影响

基本信息

批准号：
10366169
负责人：
David Feldser
金额：
$ 44.59万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-10 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366169
关键词：
Alleles Automobile Driving Biogenesis Biological Models Buffers CRISPR/Cas technology Carbon Cell Proliferation Cell Respiration Cell division Cells Chromatin Clinical Consequentialism Consumption Data Defect Development Dietary intake Disease Drug Targeting Enzymes Frequencies Gene Expression Genes Genetic Transcription Global Change Goals Growth Histone H3 Histones Human Human Cell Line Hypoxia Inducible Factor In Vitro Isotope Labeling KRAS2 gene KRASG12D Link Lipids Lung Adenocarcinoma Lysine Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolism Methionine Methyltransferase Mitochondria Molecular Molecular Abnormality Mus Mutate Mutation Oncogenic Oxidative Phosphorylation PPAR gamma Pathway interactions Patients Phenotype Post-Translational Protein Processing Protein Biosynthesis Proteomics Publishing Regulation Regulator Genes S-Adenosylhomocysteine Serine Signal Transduction Supporting Cell System Testing Therapeutic Tumor Suppressor Proteins Work cancer cell cancer type cell growth clinical efficacy dietary enzyme mechanism histone methyltransferase in vivo inhibitor lipidomics loss of function metabolomics mouse model neoplastic cell patient derived xenograft model pre-clinical programs rational design transcription factor treatment strategy tumor tumor progression

项目摘要

PROJECT SUMMARY SETD2 is mutationally inactivated in many cancer types including lung adenocarcinoma. In published work, we demonstrated that Setd2 inactivation has potent tumor promoting effects in an autochthonous mouse model of KRASG12D-driven lung adenocarcinoma. SETD2 uniquely catalyzes histone H3 lysine 36 trimethylation (H3K36me3), which marks actively transcribed gene bodies, facilitating chromatin resetting after gene transcription. In the current project, we aim to understand the provocative observation that SETD2 inactivation potently drives tumor cell proliferation due to a defect in one-carbon metabolism and activation of mTORC1 signaling. We demonstrate that SETD2 loss is associated with an enrichment in the abundance of S- adenosyl methionine (SAM) and multiple other metabolites that are part of SAM-adjacent metabolic pathways. We will test the hypothesis that the disuse of SAM that results from the lost activity of the SETD2 methyltransferase leads to SAM accumulation, enhanced one-carbon metabolism, and activation of mTORC1 signaling, all supporting cell growth and proliferation. Consistent with this hypothesis, we demonstrate that limiting dietary intake of methionine reduces KRAS-driven lung adenocarcinoma growth and reverses the effects of SETD2 inactivation. Thus, we will assess the efficacy of clinical and pre-clinical drugs that target the methionine cycle for potential synthetic lethal interactions with SETD2 deficiency. Finally, downstream of activated mTORC1 signaling we observe prominent transcriptional programs of hypoxia inducible factors (HIFs) and peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 α (PGC1α). Consistently, we observe multiple pathophysiological changes that are associated with increased activation of HIF and PGC1α transcription, such as alterations in mitochondrial biogenesis and the co-enhancement of oxidative phosphorylation and glycolytic pathways. Thus, we will test the requirement of these master transcription factors for effectuating phenotypes downstream of SETD2 inactivation.

项目概要 SETD2 在包括肺腺癌在内的许多癌症类型中发生突变失活。在发表的工作中，我们证明 Setd2 失活对本地小鼠具有有效的肿瘤促进作用 KRASG12D 驱动的肺腺癌模型。 SETD2 独特地催化组蛋白 H3 赖氨酸 36 三甲基化 (H3K36me3)，标记活跃转录的基因体，促进染色质在转录后重置基因转录。在当前的项目中，我们的目标是了解 SETD2 的挑衅性观察由于一碳代谢和激活的缺陷，失活可有效驱动肿瘤细胞增殖 mTORC1 信号传导。我们证明 SETD2 损失与 S-丰度的富集有关腺苷甲硫氨酸 (SAM) 和属于 SAM 邻近代谢途径一部分的多种其他代谢物。我们将测试以下假设：由于 SETD2 活性丧失而导致 SAM 不再使用甲基转移酶导致 SAM 积累、增强一碳代谢以及 mTORC1 激活信号传导，所有这些都支持细胞生长和增殖。与这个假设一致，我们证明限制蛋氨酸的饮食摄入量可减少 KRAS 驱动的肺腺癌生长并逆转 SETD2 失活的影响。因此，我们将评估针对以下疾病的临床和临床前药物的功效：蛋氨酸循环与 SETD2 缺陷的潜在合成致死相互作用。最后，下游激活 mTORC1 信号传导，我们观察到缺氧诱导因子的显着转录程序 (HIF) 和过氧化物酶体增殖物激活受体 γ (PPARγ) 共激活剂 1 α (PGC1α)。一贯地，我们观察与 HIF 和 PGC1α 激活增加相关的多种病理生理变化转录，例如线粒体生物发生的改变和氧化的共同增强磷酸化和糖酵解途径。因此，我们将测试这些主转录的要求影响 SETD2 失活下游表型的因素。