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.

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Acknowledgements

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.

Author information

Affiliations

  1. Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA

    • Filippos Kottakis
    • , Brandon N. Nicolay
    • , Ahlima Roumane
    • , Julia M. Nagle
    • , Myriam Boukhali
    • , Nicholas J. Dyson
    • , Wilhelm Haas
    •  & Nabeel Bardeesy
  2. Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA

    • Filippos Kottakis
    • , Ahlima Roumane
    • , Julia M. Nagle
    •  & Nabeel Bardeesy
  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Filippos Kottakis
    • , Brandon N. Nicolay
    • , Ahlima Roumane
    • , Julia M. Nagle
    • , Myriam Boukhali
    • , Nicholas J. Dyson
    • , Wilhelm Haas
    •  & Nabeel Bardeesy
  4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Rahul Karnik
    • , Hongcang Gu
    •  & Alexander Meissner
  5. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • Rahul Karnik
    • , Hongcang Gu
    •  & Alexander Meissner
  6. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Rahul Karnik
    • , Hongcang Gu
    •  & Alexander Meissner
  7. UNC, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, USA

    • Michele C. Hayward
    •  & D. Neil Hayes
  8. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Yvonne Y. Li
    • , Ting Chen
    • , Peter S. Hammerman
    •  & Kwok Kin Wong
  9. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Yvonne Y. Li
    • , Ting Chen
    • , Peter S. Hammerman
    •  & Kwok Kin Wong
  10. Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Ting Chen
    •  & Kwok Kin Wong
  11. Evans Center for Interdisciplinary Research, Department of Medicine, Mitochondria ARC, Boston University School of Medicine, Boston, Massachusetts 02118, USA

    • Marc Liesa
    •  & Orian S. Shirihai
  12. Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, UCLA David Geffen School of Medicine, Los Angeles, California 90095, USA

    • Marc Liesa
    •  & Orian S. Shirihai
  13. Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA

    • Peter S. Hammerman

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Contributions

F.K. and N.B. conceived and designed the study. F.K., A.R. and J.M.N. performed cell-based and mouse experiments. T.C. assisted with mouse experiments. F.K. and B.N.N. performed and interpreted the tracing experiments. M.B and W.H. performed proteomics. F.K. and M.L. performed the OCR measurements. M.C.H. and D.N.H. provided essential samples and data analysis. Y.Y.L. performed computational analysis. H.G. prepared WGBS libraries. R.K. and A.M. analysed and interpreted the WGBS data. P.S.H., K.K.W., O.S.S. and N.J.D. assisted with data interpretation. F.K. and N.B. wrote the manuscript with feedback from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nabeel Bardeesy.

Reviewer Information

Nature thanks M. Rehli and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figure 1, western blot source data and Supplementary Methods.

Excel files

  1. 1.

    Supplementary Data

    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.

  2. 2.

    Supplementary 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).

  3. 3.

    Supplementary Data

    This file contains Supplementary Table 3. Bisulfite conversion rates and sequencing statistics for WGBS.

  4. 4.

    Supplementary Data

    This file contains Supplementary Table 4, source data for tumour volumes in Extended Data Figures 1d, 3i, 9d, 9e, 9f, 9n, 10b.

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DOI

https://doi.org/10.1038/nature20132

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