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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：
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

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可作为共价键的底物染色质的修饰，使代谢状态和表观遗传控制。代谢控制和表观遗传之间的相互作用最近有人提出重新编程作为一种潜在的机制干细胞分化和癌症等病理过程的调节。我们确定这样的网络是细胞转化下游的主要介体 LKB1，一种重要的肿瘤抑制因子，在许多癌症中突变失活（例如肺、胰腺）。 LKB1 编码丝氨酸-苏氨酸激酶，可整合营养物质尽管 LKB1 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和通过转录、蛋白质组学和代谢分析，我们发现致癌物质 LKB1 丢失和 KRAS 激活之间的合作，改变通常同时发生在人类癌症中，营养利用的明显重新布线加剧了癌症的发生。特别是，我们证明 LKB1 失活可增强糖酵解，同时还可以引导糖酵解中间体与丝氨酸-甘氨酸-一个碳网络的耦合与生成甲基供体 S-腺苷甲硫氨酸 (SAM)。 DNA甲基转移酶协同作用（DNMT1 和 DNMT3A）上调，导致基因组 5- 甲基胞嘧啶水平。相应地，LKB1 缺陷使细胞独立于外源丝氨酸促进生长，但对丝氨酸生物合成的抑制高度敏感体外和体内 DNA 甲基化。因此，我们定义了代谢亢进状态 LKB1 缺失导致葡萄糖代谢和染色质调节的重新连接。这种状态既增强了 LKB1- 的致瘤程序，又是其所必需的。突变细胞，表明对特定患者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，目标是定义如何增强的 DNA 甲基化有助于肿瘤表型，破译 LKB1 丢失激活 SGOC 网络的信号传导和转录途径，并进一步确定靶向该通路的治疗潜力体内临床前模型。