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  LKB1 loss links serine metabolism to DNA methylation and tumorigenesis

Kottakis, F., Nicolay, B. N., Roumane, A., Karnik, R., Gu, H., Nagle, J. M., et al. (2016). LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature, 539(7629), 390-395. doi:10.1038/nature20132.

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 Creators:
Kottakis, Filippos , Author
Nicolay, Brandon N. , Author
Roumane, Ahlima , Author
Karnik, Rahul , Author
Gu, Hongcang, Author
Nagle, Julia M. , Author
Boukhali, Myriam , Author
Hayward, Michele C. , Author
Li, Yvonne Y. , Author
Chen, Ting, Author
Liesa, Marc, Author
Hammerman, Peter S. , Author
Wong, Kwok Kin , Author
Hayes, D. Neil , Author
Shirihai, Orian S. , Author
Dyson, Nicholas J. , Author
Haas, Wilhelm, Author
Meissner, Alexander1, 2, Author           
Bardeesy, Nabeel , Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA, ou_persistent22              

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Free keywords: Cancer metabolism Tumour-suppressor proteins
 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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Language(s): eng - English
 Dates: 2016-10-312016-11-17
 Publication Status: Issued
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/nature20132
 Degree: -

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 539 (7629) Sequence Number: - Start / End Page: 390 - 395 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238