LKB1 loss links serine metabolism to DNA methylation and tumorigenesis

Filippos Kottakis, Brandon N. Nicolay, Ahlima Roumane, Rahul Karnik, Hongcang Gu, Julia M. Nagle, Myriam Boukhali, Michele C. Hayward, Yvonne Y. Li, Ting Chen, Marc Liesa, Peter S. Hammerman, Kwok Kin Wong, D. Neil Hayes, Orian S. Shirihai, Nicholas J. Dyson, Wilhelm Haas, Alexander Meissner and Nabeel Bardeesy ()
Additional contact information
Filippos Kottakis: Cancer Center, Massachusetts General Hospital
Brandon N. Nicolay: Cancer Center, Massachusetts General Hospital
Ahlima Roumane: Cancer Center, Massachusetts General Hospital
Rahul Karnik: Broad Institute of MIT and Harvard
Hongcang Gu: Broad Institute of MIT and Harvard
Julia M. Nagle: Cancer Center, Massachusetts General Hospital
Myriam Boukhali: Cancer Center, Massachusetts General Hospital
Michele C. Hayward: UNC, Lineberger Comprehensive Cancer Center, Chapel Hill
Yvonne Y. Li: Brigham and Women’s Hospital and Harvard Medical School
Ting Chen: Brigham and Women’s Hospital and Harvard Medical School
Marc Liesa: Evans Center for Interdisciplinary Research, Mitochondria ARC, Boston University School of Medicine
Peter S. Hammerman: Brigham and Women’s Hospital and Harvard Medical School
Kwok Kin Wong: Brigham and Women’s Hospital and Harvard Medical School
D. Neil Hayes: UNC, Lineberger Comprehensive Cancer Center, Chapel Hill
Orian S. Shirihai: Evans Center for Interdisciplinary Research, Mitochondria ARC, Boston University School of Medicine
Nicholas J. Dyson: Cancer Center, Massachusetts General Hospital
Wilhelm Haas: Cancer Center, Massachusetts General Hospital
Alexander Meissner: Broad Institute of MIT and Harvard
Nabeel Bardeesy: Cancer Center, Massachusetts General Hospital

Nature, 2016, vol. 539, issue 7629, 390-395

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/nature20132

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