STK11/LKB1 Loss of Function Is Associated with Global DNA Hypomethylation and S-Adenosyl-Methionine Depletion in
Michael J Koenig1, Bernice A Agana2, Jacob M Kaufman3
1Department of Internal Medicine, The Ohio State University, Columbus, Ohio. David.Carbone@osumc.edu Koenig.82@osu.edu.
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.
Insights
Lung adenocarcinoma with STK11 (LKB1) loss shows widespread DNA hypomethylation. This epigenetic change is linked to altered gene expression and may impact cancer treatment strategies.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- STK11 (liver kinase B1, LKB1) is frequently mutated in lung adenocarcinoma.
- LKB1 loss of function occurs in up to 30% of lung adenocarcinoma cases.
- A 16-gene signature for LKB1 loss was previously identified.
Purpose of the Study:
- To investigate the epigenetic consequences of LKB1 loss in lung adenocarcinoma.
- To apply a 16-gene signature to TCGA lung adenocarcinoma samples.
- To uncover novel associations between LKB1 status and DNA methylation.
Main Methods:
- Application of a 16-gene signature to TCGA lung adenocarcinoma data.
- Analysis of S-adenosyl-methionine (SAM-e) levels in tumors.
- Assessment of DNA methylation patterns, including repetitive elements (RE).
- Evaluation of FOXA family protein expression and localization.
Main Results:
- LKB1-deficient tumors exhibited widespread DNA demethylation.
- Depletion of SAM-e, the substrate for DNMT1, was observed in LKB1-deficient tumors.
- Hypomethylation affected repetitive elements, altering their transcription.
- Decreased sensitivity to azacytidine was noted in LKB1-deficient tumors.
- Demethylated CpGs were enriched for FOXA binding sites, with FOXA expression dependent on LKB1.
Conclusions:
- LKB1 loss drives global hypomethylation in a significant subset of lung adenocarcinomas.
- This epigenetic dysregulation involves SAM-e depletion and altered RE transcription.
- Findings have implications for epigenetic therapy and immunotherapy in LKB1-mutant lung cancers.
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