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Nature. 2016 Nov 17;539(7629):390-395. doi: 10.1038/nature20132. Epub 2016 Oct 31.

LKB1 loss links serine metabolism to DNA methylation and tumorigenesis.

Kottakis F1,2,3, Nicolay BN1,3, Roumane A1,2,3, Karnik R4,5,6, Gu H4,5,6, Nagle JM1,2,3, Boukhali M1,3, Hayward MC7, Li YY8,9, Chen T8,9,10, Liesa M11,12, Hammerman PS8,9,13, Wong KK8,9,10, Hayes DN7, Shirihai OS11,12, Dyson NJ1,3, Haas W1,3, Meissner A4,5,6, Bardeesy N1,2,3.

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Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
UNC, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Evans Center for Interdisciplinary Research, Department of Medicine, Mitochondria ARC, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, UCLA David Geffen School of Medicine, Los Angeles, California 90095, USA.
Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.


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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