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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：
10539347
负责人：
David Feldser
金额：
$ 43.91万
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/10539347
关键词：
Alleles Automobile Driving Biogenesis Biological Models Buffers CRISPR/Cas technology Carbon Cell Proliferation Cell Respiration Cell division Cells Chromatin Clinical 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 LoxP-flanked allele Lung Adenocarcinoma Lysine Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolism Methionine Methylation Methyltransferase Mitochondria Molecular Molecular Abnormality Mus Mutate Mutation Oncogenic Oxidative Phosphorylation PPAR gamma Pathway interactions Patients Pharmaceutical Preparations Phenotype Post-Translational Protein Processing Protein Biosynthesis Proteomics Publishing Regulation Regulator Genes S-Adenosylhomocysteine S-Adenosylmethionine Serine Signal Transduction Supporting Cell System Testing Therapeutic Tumor Promotion Tumor Suppressor Proteins Work cancer cell cancer type cell growth clinical efficacy dietary dietary restriction efficacy evaluation enzyme mechanism histone methyltransferase in vivo inhibitor lipidomics loss of function metabolomics mouse model neoplastic cell novel therapeutic intervention patient derived xenograft model pre-clinical programs rational design synthetic lethal interaction transcription factor 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.

项目总结