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Cited by 18Epigenetics and DNA MethylationLung Cancer Treatments and MutationsChromatin Remodeling and Cancer

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STK11/LKB1 Loss of Function Is Associated with Global DNA Hypomethylation and S -Adenosyl-Methionine Depletion in Human Lung Adenocarcinoma

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Koenig, Michael J., Agana, Bernice A., Kaufman, Jacob M., Sharpnack, Michael F., Wang, Walter Z., Weigel, Christoph, Navarro, Fabio C.P., Amann, Joseph M., Cacciato, Nicole, Arasada, Rajeswara Rao, Gerstein, Mark B., Wysocki, Vicki H., Oakes, Christopher, Carbone, David P.·2021·Cancer Research
DOI 10.1158/0008-5472.can-20-3199PMC PMC8373682

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Abstract

STK11 (liver kinase B1, LKB1) is the fourth most frequently mutated gene in lung adenocarcinoma, with loss of function observed in up to 30% of all cases. Our previous work identified a 16-gene signature for LKB1 loss of function through mutational and nonmutational mechanisms. In this study, we applied this genetic signature to The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples and discovered a novel association between LKB1 loss and widespread DNA demethylation. LKB1-deficient tumors showed depletion of S-adenosyl-methionine (SAM-e), which is the primary substrate for DNMT1 activity. Lower methylation following LKB1 loss involved repetitive elements (RE) and altered RE transcription, as well as decreased sensitivity to azacytidine. Demethylated CpGs were enriched for FOXA family consensus binding sites, and nuclear expression, localization, and turnover of FOXA was dependent upon LKB1. Overall, these findings demonstrate that a large number of lung adenocarcinomas exhibit global hypomethylation driven by LKB1 loss, which has implications for both epigenetic therapy and immunotherapy in these cancers. Significance: Lung adenocarcinomas with LKB1 loss demonstrate global genomic hypomethylation associated with depletion of SAM-e, reduced expression of DNMT1, and increased transcription of repetitive elements.

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Metadata

Authors
Koenig, M. J., Agana, B. A., Kaufman, J. M., Sharpnack, M. F., Wang, W. Z., Weigel, C., Navarro, F. C. P., Amann, J. M., Cacciato, N., Arasada, R. R., Gerstein, M. B., Wysocki, V. H., Oakes, C., & Carbone, D. P.
Affiliations
  • The Ohio State University (US)
  • Duke University (US)
  • 4Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut.
  • Yale University (US)
Corresponding author
Carbone, David P.
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2021-05-27
Volume
81
Issue
16
Pages
4194-4204
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-20-3199
PMC
PMC8373682
OpenAlex
W3164877040
Cited by
18
References
6
Citations by year
2026: 3 · 2025: 8 · 2024: 4 · 2023: 2 · 2022: 1
FWCI
0.55
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (UG1 CA233259, P30 CA016058, S10 OD018056)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
STK11, LKB1, lung adenocarcinoma, DNA hypomethylation, global DNA demethylation, DNMT1, repetitive elements, FoxA, epigenetic therapy, immunotherapy, loss of function
MeSH terms
AMP-Activated Protein Kinase Kinases, Adenocarcinoma, Cell Line, Cell Survival, Humans, Lung Neoplasms, Methionine, Mutation, Genes, ras, Repetitive Sequences, Nucleic Acid, S-Adenosylmethionine, Cluster Analysis, Proto-Oncogene Proteins p21(ras), CpG Islands, DNA Methylation, Computational Biology, Oligonucleotide Array Sequence Analysis, Databases, Genetic, Epigenesis, Genetic

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