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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：
10337194
负责人：
NABEEL El-BARDEESY
金额：
$ 47.06万
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/10337194
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

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.

在细胞代谢中产生的中间体也充当共价结合的底物。染色质的修饰，使代谢状态的潜在耦合，表观遗传控制代谢控制和表观遗传之间的相互作用最近有人提出，重编程是一种潜在的机制，调节干细胞分化和用于病理过程如癌症。我们确定这样的网络作为细胞转化下游的主要介质， LKB 1，一种重要的肿瘤抑制因子，在许多癌症中突变失活 (e.g.肺、胰腺）。LKB 1编码一种丝氨酸-苏氨酸激酶，可用性，代谢和生长，虽然LKB 1依赖的机制肿瘤抑制仍然难以捉摸。通过开发原代上皮细胞模型，通过转录、蛋白质组学和代谢分析，我们发现， LKB 1缺失和KRAS激活之间的合作，通常同时发生的改变在人类癌症中，是由营养利用的明显重新布线所推动的。我们尤其证明LKB 1失活增强糖酵解，同时也引导糖酵解中间体的丝氨酸-甘氨酸-一个碳网络耦合生成甲基供体S-腺苷甲硫氨酸（SAM）。DNA甲基转移酶（DNMT 1和DNMT 3A）上调，导致基因组5- 甲基胞嘧啶水平。相应地，LKB 1缺陷使得细胞不依赖于外源丝氨酸的生长，但高度敏感的丝氨酸生物合成的抑制，体外和体内DNA甲基化。因此，我们定义了一种高代谢状态， LKB 1的丢失，LKB 1连接葡萄糖代谢和染色质调节的重新布线。这种状态既增强了LKB 1的致瘤程序，也是其关键所需。突变细胞，提示在确定的患者中进行治疗干预的新点子集在这里，我们将以这些令人兴奋的发现为基础，目标是确定这是如何实现的。增强的DNA甲基化有助于肿瘤表型， LKB 1缺失激活SGOC网络的信号传导和转录途径，并进一步确定靶向该途径的治疗潜力，体内临床前模型。