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STK11/LKB1 Loss of Function Is Associated with Global DNA Hypomethylation and S-Adenosyl-Methionine Depletion in Human Lung Adenocarcinoma.
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.
Afiliación
  • Koenig MJ; Department of Internal Medicine, The Ohio State University, Columbus, Ohio. David.Carbone@osumc.edu Koenig.82@osu.edu.
  • Agana BA; Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio.
  • Kaufman JM; Department of Medicine, Duke University, Durham, North Carolina.
  • Sharpnack MF; Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
  • Wang WZ; Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
  • Weigel C; Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
  • Navarro FCP; Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut.
  • Amann JM; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.
  • Cacciato N; Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
  • Arasada RR; Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
  • Gerstein MB; Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
  • Wysocki VH; Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut.
  • Oakes C; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.
  • Carbone DP; Department of Computer Science, Yale University, New Haven, Connecticut.
Cancer Res ; 81(16): 4194-4204, 2021 08 15.
Article en En | MEDLINE | ID: mdl-34045189
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: S-Adenosilmetionina / Adenocarcinoma / Metilación de ADN / Quinasas de la Proteína-Quinasa Activada por el AMP / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cancer Res Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: S-Adenosilmetionina / Adenocarcinoma / Metilación de ADN / Quinasas de la Proteína-Quinasa Activada por el AMP / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Cancer Res Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos