Functions of the LKB1 tumor suppressor in control in metabolism and epigenetics

LKB1肿瘤抑制因子在代谢和表观遗传学控制中的功能

基本信息

批准号：
10524240
负责人：
NABEEL El-BARDEESY
金额：
$ 11.65万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524240
关键词：
Amines Anabolism Automobile Driving Carbon Cell model Cells Cellular Metabolic Process Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Coupled Coupling DNA Maintenance DNA Methylation DNA Modification Methylases DNA biosynthesis Data Elements Epigenetic Process Epithelial Cells Exhibits Family Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genetically Engineered Mouse Genome Genomics Glucose Glutamine Glycine Glycolysis Goals Growth Human Hypersensitivity In Vitro Interferons KRAS2 gene Link Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mediator of activation protein Metabolic Metabolic Control Metabolism Methods Methylation Modeling Mutation Nutrient Oncogenic Pancreas Pathologic Processes Pathway interactions Pharmacology Phenotype Phosphorylation Phosphotransferases Pre-Clinical Model Process Protein-Serine-Threonine Kinases Proteomics Regulation Research Personnel Retrotransposon S-Adenosylmethionine STK11 gene Serine Signal Pathway Signal Transduction Specimen System Testing Therapeutic Therapeutic Intervention Tumor Suppression Tumor Suppressor Proteins base bisulfite sequencing cancer cell cancer type cell transformation chromatin modification clinical translation clinically significant cytotoxic cytotoxicity defined contribution demethylation epigenome genome editing genome-wide glucose metabolism immune checkpoint in vivo in vivo Model inhibitor insight lung cancer cell member mutant novel pancreatic cancer cells patient derived xenograft model patient subsets phase 1 study phosphoproteomics programs resistance mechanism response stem cell differentiation tumor tumorigenesis tumorigenic uptake whole genome

Amines Anabolism Automobile Driving Carbon Cell model Cells Cellular Metabolic Process Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Coupled Coupling DNA Maintenance DNA Methylation DNA Modification Methylases DNA biosynthesis Data Elements Epigenetic Process Epithelial Cells Exhibits Family Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genetically Engineered Mouse Genome Genomics Glucose Glutamine Glycine Glycolysis Goals Growth Human Hypersensitivity In Vitro Interferons KRAS2 gene Link Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mediating Mediator of activation protein Metabolic Metabolic Control Metabolism Methods Methylation Modeling Mutation Nutrient Oncogenic Pancreas Pathologic Processes Pathway interactions Pharmacology Phenotype Phosphorylation Phosphotransferases Pre-Clinical Model Process Protein-Serine-Threonine Kinases Proteomics Regulation Research Personnel Retrotransposon S-Adenosylmethionine STK11 gene Serine Signal Pathway Signal Transduction Specimen System Testing Therapeutic Therapeutic Intervention Tumor Suppression Tumor Suppressor Proteins base bisulfite sequencing cancer cell cancer type cell transformation chromatin modification clinical translation clinically significant cytotoxic cytotoxicity defined contribution demethylation epigenome genome editing genome-wide glucose metabolism immune checkpoint in vivo in vivo Model inhibitor insight lung cancer cell member mutant novel pancreatic cancer cells patient derived xenograft model patient subsets phase 1 study phosphoproteomics programs resistance mechanism response stem cell differentiation tumor tumorigenesis tumorigenic uptake whole genome

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项目摘要

Intermediates generated in cell metabolism also serve as substrates for covalent modification of chromatin, enabling the potential coupling of metabolic states and epigenetic control. This interplay between metabolic control and epigenetic reprogramming has been recently been proposed as a potential mechanism for regulation of stem cell differentiation and for pathologic processes such as cancer. We identify such a network as a major mediator of cell transformation downstream of the LKB1, an important tumour suppressor that is mutationally inactivated in many cancers (e.g. lung, pancreas). LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, although the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing primary epithelial cell models and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation, alterations commonly coinciding in human cancer, is fueled by pronounced rewiring of nutrient utilization. In particular, we demonstrate that LKB1 inactivation potentiates glycolysis while also channeling glycolytic intermediates to the serine-glycine-one carbon network coupled to generation of the methyl donor S-adenosylmethionine (SAM). In concert, DNA methyltransferases (DNMT1 and DNMT3A) are upregulated, leading to global elevation in genomic 5- methylcytosine levels. Correspondingly, LKB1 deficiency renders cells independent of exogenous serine for growth, but highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from loss of LKB1 that links rewiring of glucose metabolism and chromatin regulation. This state both potentiates and is critically required for the tumorigenic program of LKB1- mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets. Here, we will build on these exciting findings, with the goals of defining how this enhanced DNA methylation contributes to the tumor phenotypes, deciphering the signaling and transcriptional pathways by which LKB1 loss activates to SGOC network, and further establishing the therapeutic potential of targeting this pathway in relevant in vivo preclinical models.

细胞代谢中产生的中间体也充当共价的底物修饰染色质，使代谢状态的潜在耦合和表观遗传控制。代谢控制和表观遗传学之间的这种相互作用最近已提出重新编程作为潜在的机制调节干细胞分化和病理过程（例如癌症）。我们将这种网络确定为下游细胞转换的主要介体 LKB1，一种重要的肿瘤抑制剂，在许多癌症中被突变失活（例如肺，胰腺）。 LKB1编码丝氨酸 - 苏氨酸激酶，该激酶整合营养素尽管LKB1依赖性的机制，可用性，代谢和增长肿瘤抑制仍然难以捉摸。通过开发主要的上皮细胞模型和采用转录，蛋白质组学和代谢分析，我们发现致癌 LKB1损失与KRAS激活之间的合作，通常是重合的变化在人类癌症中，养分利用率的明显重新布线助长了。特别是我们证明LKB1失活增强了糖酵解，同时也引导糖酵解中间体到丝氨酸 - 丝氨酸一碳网络，耦合到代甲基供体S-腺苷硫氨酸（SAM）。在音乐会上，DNA甲基转移酶（DNMT1和DNMT3A）上调，导致基因组5-的全球升高甲基胞嘧啶水平。相应地，LKB1缺乏使细胞独立于外源丝氨酸的生长，但对抑制丝氨酸生物合成和高度敏感在体外和体内DNA甲基化。因此，我们定义了产生的多代谢态从LKB1的丢失来连接葡萄糖代谢和染色质调节的连接。该状态既具有增强作用又是LKB1-肿瘤性计划所必需的突变细胞，提示定义患者的新型治疗干预点子集。在这里，我们将基于这些令人兴奋的发现，其目标是定义如何增强的DNA甲基化有助于肿瘤表型，破译 LKB1损失激活为SGOC网络的信号传导和转录途径，并进一步确立针对这一途径相关的治疗潜力体内临床前模型。