LKB1 loss links serine metabolism to DNA methylation and tumorigenesis
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
LKB1 activates AMPK and has been linked to serine metabolism and tumorigenesis.
“Furthermore, the tumor suppressor LKB1, which activates the energy sensor and metabolic regulator AMPK, has been linked to serine metabolism and induction of tumorigenesis45.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [45]
Concurrent KRAS and LKB1 mutations confer vulnerabilities in pancreatic cancer, but the mechanisms differ from those in lung cancer.
“Concurrent mutations in KRAS and LKB1 also confer vulnerabilities in pancreatic cancer, but the mechanisms are different from those in lung cancer45.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [45]
In pancreatic cancer, concurrent KRAS and LKB1 mutations support tumor growth by activating serine synthesis and increasing DNA methylation.
“In pancreatic cancer, such concurrent mutations support tumor growth by activating serine synthesis and increasing DNA methylation.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [45]
Epigenetic reprogramming upon LKB1 loss in KRAS-mutant cells is fueled by a metabolic network that promotes increased flux of glucose-derived carbon towards serine biosynthesis and the methionine salvage pathway, bolstering synthesis of SAM.
“Epigenetic reprogramming upon LKB1 loss in KRAS-mutant cells is further fueled by a metabolic network, that promotes increased flux of glucose-derived carbon towards serine biosynthesis and the methionine salvage pathway, bolstering synthesis of S-adenosyl methionine (SAM), a critical substrate for DNA methylation87.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [87]
Generation of SAM via this pathway, coupled with up-regulation of DNA methyl-transferases, underpins an increase in global levels of CpG methylation in KL cells that is critical for tumor maintenance.
“Generation of SAM via this pathway, coupled with up-regulation of DNA methyl-transferases, underpins an increase in global levels of CpG methylation in KL cells that is critical for tumor maintenance.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [87]
In LKB1-deficient cells, greater EZH2 and DNMT1 methyltransferase activity silences STING; this is partly because glucose is diverted to serine biosynthesis, raising SAM.
“Silencing of STING in this context is triggered by enhanced activity of the EZH2 and DNMT1 methyltransferases due – at least in part- to increased production of SAM through diversion of glucose towards the serine biosynthetic pathway in LKB1-deficient cells87, 136.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [87]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 68 · Cited by 348
Research works printed but not linked: 4
- [5]Bardeesy N Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse Proc Natl Acad Sci USA 103 5947 5952 2006 16585505 PMC1458678
- [7]Ji H LKB1 modulates lung cancer differentiation and metastasis Nature 448 807 810 2007 17676035
- [13]Mehrmohamadi M Liu X Shestov AA Locasale JW Characterization of the usage of the serine metabolic network in human cancer Cell Rep 9 1507 1519 2014 25456139 PMC4317399
- [21]Ting L Rad R Gygi SP Haas W MS3 eliminates ratio distortion in isobaric multiplexed quantitative proteomics Nat Methods 8 937 940 2011 21963607 PMC3205343
- Authors
- Kottakis, F., Nicolay, B. N., Roumane, A., Karnik, R., Gu, H., Nagle, J. M., Boukhali, M., Hayward, M. C., Li, Y. Y., Chen, T., Liesa, M., Hammerman, P. S., Wong, K. K., Hayes, D. N., Shirihai, O. S., Dyson, N. J., Haas, W., Meissner, A., & Bardeesy, N.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- University of North Carolina at Chapel Hill (US)
- Brigham and Women's Hospital (US)
- Boston University (US)
- Corresponding author
- Bardeesy, Nabeel
- ORCID
- Venue
- Nature
- Published
- 2016-10-31
- Volume
- 539
- Issue
- 7629
- Pages
- 390-395
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5988435
- OpenAlex
- W2540090384
- Cited by
- 348
- References
- 68
- Citations by year
- 2026: 22 · 2025: 30 · 2024: 47 · 2023: 40 · 2022: 33 · 2021: 44 · 2020: 35 · 2019: 35 · 2018: 30 · 2017: 28 · 2016: 4
- FWCI
- 16.80
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-11-06)
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Hirshberg Foundation for Pancreatic Cancer Research
- National Institutes of Health (P50CA1270003)
- National Cancer Institute (R01CA133557, P01CA117969)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099618)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- LKB1, STK11, KRAS, serine metabolism, DNA methylation, mTOR, S-adenosylmethionine, DNA methyltransferases, retrotransposon silencing, carcinogenesis, metabolic reprogramming, epigenetic regulation, pancreatic cancer, metabolic vulnerability
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Transaminases, Animals, Cell Transformation, Neoplastic, Chromatin, DNA (Cytosine-5-)-Methyltransferases, Enzyme Inhibitors, Epithelial Cells, Glycine, Glycolysis, Humans, Pancreatic Ducts, S-Adenosylmethionine, Serine, Genes, Tumor Suppressor, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, Retroelements, Cell Culture Techniques, DNA Methylation, Gene Silencing, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
