LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis
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ABSTRACT:
PROVIDER: PRJNA340375 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4080680_1.fastq.gz | Fastqsanger.gz | |||
| SRR4080680_2.fastq.gz | Fastqsanger.gz | |||
| SRR4080690_1.fastq.gz | Fastqsanger.gz | |||
| SRR4080690_2.fastq.gz | Fastqsanger.gz | |||
| SRR4080700_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Intermediary metabolism generates substrates for covalent modification of chromatin, enabling potential coupling of metabolic states and epigenetic control. Here, we identify such a network as a major component of oncogenic transformation downstream of the LKB1 tumour suppressor. LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, however the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing genetically engineered mouse and 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 mTOR-dependent induction of the serine-glycine-one carbon network coupled to S-adenosylmethionine generation. In concert, DNA methyltransferases (DNMT1, DNMT3A) are upregulated, leading to elevation in genomic 5-methylcytosine levels, with particular enrichment at retrotransposon elements, associated with silencing of retrotransposon transcription. Correspondingly, LKB1 deficiency renders cells highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from LKB1 loss and KRAS activation that fuels changes in the epigenetic landscape. This state is critically required for the tumourigenic program of LKB1-mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets.
2016-10-24 | GSE86144 | GEO
Project description:Intermediary metabolism generates substrates for covalent modification of chromatin, enabling potential coupling of metabolic states and epigenetic control. Here, we identify such a network as a major component of oncogenic transformation downstream of the LKB1 tumour suppressor. LKB1 encodes a serine-threonine kinase that integrates nutrient availability, metabolism and growth, however the mechanisms for LKB1-dependent tumour suppression remain elusive. By developing genetically engineered mouse and 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 mTOR-dependent induction of the serine-glycine-one carbon network coupled to S-adenosylmethionine generation. In concert, DNA methyltransferases (DNMT1, DNMT3A) are upregulated, leading to elevation in genomic 5-methylcytosine levels, with particular enrichment at retrotransposon elements, associated with silencing of retrotransposon transcription. Correspondingly, LKB1 deficiency renders cells highly sensitive to inhibition of serine biosynthesis and DNA methylation in vitro and in vivo. Thus, we define a hypermetabolic state resulting from LKB1 loss and KRAS activation that fuels changes in the epigenetic landscape. This state is critically required for the tumourigenic program of LKB1-mutant cells, suggesting novel points of therapeutic intervention in defined patient subsets.
2016-10-24 | GSE86143 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-10-24 | GSE86145 | GEO
Project description:Heterozygous germ-line mutations in the LKB1 (STK11) gene cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by hamartomatous polyposis of the gastrointestinal tract and an increased risk of colorectal, breast, ovarian, testicular and cervical cancer. To model the effects of LKB1 mutation in mammary tumourigenesis, we have used a conditional gene targeting strategy to generate a mouse in which exons 4-7 of the Lkb1 gene encoding the kinase domain of the protein are deleted specifically in the mammary gland. Mammary gland tumours arise in these mice with a latency of 46-85 weeks and occur in the thoracic or inguinal glands. These mammary gland tumours were characterised as Grade 2 invasive ductal carcinomas or solid papillary carcinomas and resemble those arising in PJS patients. This mouse model of Lkb1 deficiency provides a potentially useful tool to investigate the role of Lkb1 in tumourigenesis and to guide the development of therapeutic approaches
2009-09-21 | E-TABM-643 | biostudies-arrayexpress
Project description:LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis [RNA-seq]
| PRJNA340411 | ENA
Project description:LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis [bisulfite-seq]
| PRJNA340412 | ENA
Project description:LKB1 is a tumor suppressor lost in approximately 30% of lung adenocarcinomas. It is a serine-threonine kinase involved in regulating metabolism, proliferation, and cell polarity. We have characterized its association with mRNA expression profiles in resected tumors and in cell lines, but little is known about the direct effects of LKB1 on the regulation of these genes. This study investigates the effects of LKB1 activity on mRNA expression in two LKB1-mutant lung adenocarcinoma cell lines, H2122 and A549. Wild-type LKB1 has been stably expressed in these cell lines using a pBABE retrovirus as well as an empty pBABE control and a kinase-dead mutant of LKB1 (K78I) control (Addgene). Samples submitted are two cell lines, three experimental conditions, and three replicates, for a total of 17 samples (one sample was excluded for poor RNA quality). Gene expression of these samples are analyzed to determine transcriptional regulatory effects of LKB1 expression. Results of this analysis are compared to our analysis of resected human tumors to determine gene patterns that are differentially expressed between LKB1-deficient and LKB1-wild-type tumors whose expression is also affected by restoration of LKB1 in vitro. RMA gene expression was taken from two cell lines stably expressing LKB1 or controls of K78I mutant LKB1 or empty pBABE vector. Log2 average expression differences are calculated and compared to results from analysis of gene expression associated with LKB1 loss in resected human tumors.
2013-10-01 | E-GEOD-51266 | biostudies-arrayexpress
Project description:The goals of this study was to compare hepatic transcriptome profiling (RNA-seq) in wild type (WT) and Liver Kinase B1 knock out (LKB1 KO) mice Methods: hepatocyte mRNA profiles of 10-weeks-old WT and LKB1 KO mice were generated, in triplicate, using Illumina NextSeq technology. The sequence reads that passed quality filters were analyzed at the gene level.
2022-01-28 | GSE192404 | GEO
Project description:The serine/threonine kinase LKB1 is a tumor suppressor gene which also plays key roles in metabolic function in peripheral tissues through its direct phosphorylation and activation of the AMP-activated protein kinase (AMPK). The LKB1/AMPK pathway plays key roles in the liver in suppressing transcriptional programs of gluconeogenesis and lipogenesis, and hepatic LKB1 is required for the ability of the type 2 diabetes agent metformin to lower blood glucose levels in mice. To more broadly define how the LKB1/AMPK pathway controls hepatic metabolism, transcriptional profiling was employed using mice with an inducible liver-specific deletion of Lkb1. Unexpectedly, LKB1/AMPK signaling broadly controls the expression of many phase I xenobiotic metabolism genes, including several members of the cytochrome P450 family. In particular, expression of CYP2E1, an important mediator of drug detoxification, was markedly reduced upon LKB1 loss. LKB1 liver-specific knockout mice exposed to hepatocarcinogens, exhibited marked resistance to carcinogen-induced hepatocyte apoptosis, proliferation, senescence, and liver fibrosis and tumorigenesis.
2019-05-01 | GSE21984 | GEO
Project description:Intermediary metabolism generates substrates for chromatin modification, enabling the potential coupling of metabolic and epigenetic states. Here we identify a network linking metabolic and epigenetic alterations that is central to oncogenic transformation downstream of the liver kinase B1 (LKB1, also known as STK11) tumour suppressor, an integrator of nutrient availability, metabolism and growth. By developing genetically engineered mouse models and primary pancreatic epithelial cells, and employing transcriptional, proteomics, and metabolic analyses, we find that oncogenic cooperation between LKB1 loss and KRAS activation is fuelled by pronounced mTOR-dependent induction of the serine-glycine-one-carbon pathway coupled to S-adenosylmethionine generation. At the same time, DNA methyltransferases are upregulated, leading to elevation in DNA methylation with particular enrichment at retrotransposon elements associated with their transcriptional silencing. Correspondingly, LKB1 deficiency sensitizes cells and tumours to inhibition of serine biosynthesis and DNA methylation. Thus, we define a hypermetabolic state that incites changes in the epigenetic landscape to support tumorigenic growth of LKB1-mutant cells, while resulting in potential therapeutic vulnerabilities.
| S-EPMC5988435 | biostudies-literature