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Updated: Feb 17, 2026
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Gene promoter hypermethylation in mouse lung tumors
Brian R Vuillemenot1, Julie A Hutt, Steven A Belinsky
1Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive Southeast, Albuquerque, NM 87108, USA.
Abstract:
The mouse is a good model for evaluating the efficacy of chemopreventive agents for lung cancer. Gene silencing by promoter hypermethylation is a critical component for the development and progression of lung cancer and an emerging target for preventive intervention by demethylating agents. Genes methylated in mouse lung tumors could serve as biomarkers to evaluate the effectiveness of demethylating agents for preventing lung cancer and causing gene reexpression in vivo. The purpose of the current study was to evaluate a panel of genes inactivated by promoter hypermethylation in human lung cancer for silencing by this epigenetic mechanism in murine lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), cigarette smoke, or arising spontaneously. Cadherin-13, estrogen receptor-alpha, progesterone receptor, and runt-related transcription factor-3 were frequently methylated in mouse lung tumor-derived cell lines, whereas cadherin-1 and suppressor of cytokine signaling-1 were not. Methylation within these four genes was associated with lack of expression that could be restored after treatment with 5-aza-2'-deoxycytidine and with methylation within the CpG island of each gene. Methylation-specific PCR revealed that methylation of these four genes occurred at prevalences of 24% to 69% in primary lung tumors arising spontaneously or induced by exposure to cigarette smoke or NNK. Estrogen receptor-alpha methylation was more frequent in spontaneously occurring lung cancer than cigarette smoke-induced or NNK-induced lung cancer, whereas runt-related transcription factor-3 showed the opposite relationship. Thus, genes can be targeted for inactivation by methylation, depending on exposure history. This study indicates that methylation events frequently observed in human lung cancer are recapitulated in the mouse model and identifies four potential biomarkers for assessing intervention approaches for reversing epigenetically mediated gene silencing.
Insights
This study identifies four key genes methylated in mouse lung tumors, serving as potential biomarkers for evaluating demethylating agents in lung cancer prevention and gene reexpression therapies.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Promoter hypermethylation causes gene silencing, crucial in lung cancer development and progression.
- Demethylating agents offer a preventive strategy targeting epigenetic modifications.
- Mouse models are valuable for assessing chemopreventive agents' efficacy in lung cancer.
Purpose of the Study:
- To investigate promoter hypermethylation-induced gene silencing in mouse lung tumors.
- To evaluate specific genes (Cadherin-13, estrogen receptor-alpha, progesterone receptor, runt-related transcription factor-3) for methylation in mouse lung tumors induced by NNK, cigarette smoke, or arising spontaneously.
- To identify potential biomarkers for assessing demethylating agent interventions.
Main Methods:
- Analysis of gene promoter methylation in mouse lung tumor cell lines and primary tumors.
- Treatment of cell lines with 5-aza-2'-deoxycytidine to assess gene reexpression.
- Methylation-specific PCR to determine gene methylation prevalence in different tumor types.
- Comparison of methylation patterns across spontaneously occurring, cigarette smoke-induced, and NNK-induced lung tumors.
Main Results:
- Cadherin-13, estrogen receptor-alpha, progesterone receptor, and runt-related transcription factor-3 were frequently methylated and silenced in mouse lung tumors.
- Methylation correlated with gene silencing, which was reversible upon treatment with 5-aza-2'-deoxycytidine.
- Methylation prevalence ranged from 24% to 69% in primary lung tumors.
- Estrogen receptor-alpha methylation was higher in spontaneous tumors, while runt-related transcription factor-3 methylation was higher in induced tumors.
Conclusions:
- Epigenetic gene silencing mechanisms in human lung cancer are recapitulated in mouse models.
- Four genes (Cadherin-13, estrogen receptor-alpha, progesterone receptor, runt-related transcription factor-3) are validated as potential biomarkers for lung cancer prevention research.
- These biomarkers can assess the effectiveness of demethylating agents in reversing epigenetically mediated gene silencing in vivo.
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