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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We thank A. Kimmelman, K. Patra, L. J. Etchegaray, and R. Mostoslavsky for comments on the manuscript, and P. Foltopoulou, B. Martinez and Bardeesy laboratory members for advice. N.B. holds the Gallagher Endowed Chair in Gastrointestinal Cancer Research and received support from the Granara-Skerry Trust, the Linda J. Verville Foundation and the Begg Family, and grants from the NIH (P01 CA117969-07, R01 CA133557-05). F.K. is supported by a Hirshberg Foundation Career Development Award. F.K. and N.B. were supported by NIH grant P50CA1270003 and are members of the Andrew Warshaw Institute.
Extended data figures
This file contains Supplementary Table 1, Metabolic signatures (KEGG) regulated by LKB1. Metabolic KEGG genesets that are significantly enriched upon LKB1 deletion. GSEA was performed using both RNA-sequencing and proteomics data.
This file contains Supplementary Table 2, a curated list of S-adenosyl-methionine utilizing enzymes. A List of 183 SAM-utilizing methyltransferases with expression values for K, KL and rescue cells (RNA) or K and KL cells (protein).
This file contains Supplementary Table 3. Bisulfite conversion rates and sequencing statistics for WGBS.
This file contains Supplementary Table 4, source data for tumour volumes in Extended Data Figures 1d, 3i, 9d, 9e, 9f, 9n, 10b.