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LKB1 loss links serine metabolism to DNA methylation and tumorigenesis

ABSTRACT: Proteome maps were generated for pancreatic ductal epithelial cells from LSL KRASG12D/+ and LSL KRASG12D/+;LKB1l/l mice. The cells were isolated from the mice, and genetic lesions were induced in vitro by infection with Ade-Cre. Proteome maps were done with multiplexed proteomics using TMT10plex technology. Mass spectrometry was done on an Orbitrap Fusion using the SPS-MS3 method. Samples were TMT labeled as follows: K1-1 (126), K1-2 (129n), K2-1 (127n), K2-2 (129c), KL1-1 (127c), KL1-2 (130n), KL2-1 (128n), KL2-2 (130c).

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Nabeel Bardeesy

PROVIDER: MSV000082186 | MassIVE | Tue Mar 20 08:55:00 GMT 2018

REPOSITORIES: MassIVE

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LKB1 loss links serine metabolism to DNA methylation and tumorigenesis.

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.

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LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis

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LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis [RNA-seq]

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.

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LKB1 loss links the serine metabolic network to DNA methylation and tumourigenesis

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