Related Experiment Video
Updated: May 24, 2026
The Soft Agar Colony Formation Assay
Published on: October 27, 2014
Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing
Daniela S Basseres1, Francesco D'Alò, Beow Y Yeap
1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; University of São Paulo, São Paulo, SP, Brazil.
Purpose:
We sought to determine the mechanisms of downregulation of the airway transcription factor Foxa2 in lung cancer and the expression status of Foxa2 in non-small-cell lung cancer (NSCLC).
Methods:
A series of 25 lung cancer cell lines were evaluated for Foxa2 protein expression, FOXA2 mRNA levels, FOXA2 mutations, FOXA2 copy number changes and for evidence of FOXA2 promoter hypermethylation. In addition, 32 NSCLCs were sequenced for FOXA2 mutations and 173 primary NSCLC tumors evaluated for Foxa2 expression using an immunohistochemical assay.
Results:
Out of the 25 cell lines, 13 (52%) had undetectable FOXA2 mRNA. The expression of FOXA2 mRNA and Foxa2 protein were congruent in 19/22 cells (p = 0.001). FOXA2 mutations were not identified in primary NSCLCs and were infrequent in cell lines. Focal or broad chromosomal deletions involving FOXA2 were not present. The promoter region of FOXA2 had evidence of hypermethylation, with an inverse correlation between FOXA2 mRNA expression and presence of CpG dinucleotide methylation (p < 0.0001). In primary NSCLC tumor specimens, there was a high frequency of either absence (42/173, 24.2%) or no/low expression (96/173, 55.4%) of Foxa2. In 130 patients with stage I NSCLC there was a trend towards decreased survival in tumors with no/low expression of Foxa2 (HR of 1.6, 95%CI 0.9-3.1; p = 0.122).
Conclusions:
Loss of expression of Foxa2 is frequent in lung cancer cell lines and NSCLCs. The main mechanism of downregulation of Foxa2 is epigenetic silencing through promoter hypermethylation. Further elucidation of the involvement of Foxa2 and other airway transcription factors in the pathogenesis of lung cancer may identify novel therapeutic targets.
Insights
Loss of Foxa2 expression is common in lung cancer, primarily due to epigenetic silencing via promoter hypermethylation. This finding suggests Foxa2 may be a therapeutic target in non-small-cell lung cancer (NSCLC).
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- Transcription factors regulate gene expression crucial for cellular function.
- Foxa2 is an airway transcription factor implicated in lung development and homeostasis.
- Dysregulation of transcription factors is a hallmark of cancer development.
Purpose of the Study:
- To investigate the mechanisms driving the downregulation of the airway transcription factor Foxa2 in lung cancer.
- To determine the expression status of Foxa2 in non-small-cell lung cancer (NSCLC).
Main Methods:
- Assessed Foxa2 protein and mRNA levels, mutations, copy number, and promoter hypermethylation in 25 lung cancer cell lines.
- Sequenced FOXA2 in 32 NSCLCs and evaluated Foxa2 expression via immunohistochemistry in 173 primary NSCLC tumors.
Main Results:
- 52% of cell lines showed undetectable FOXA2 mRNA; expression was congruent between mRNA and protein.
- No FOXA2 mutations or chromosomal deletions were found in primary NSCLCs.
- Promoter hypermethylation inversely correlated with FOXA2 mRNA levels (p < 0.0001).
- Absence or low expression of Foxa2 occurred in 80% of primary NSCLC tumors.
- A trend towards decreased survival was observed in NSCLC patients with low Foxa2 expression (p = 0.122).
Conclusions:
- Loss of Foxa2 expression is frequent in lung cancer cell lines and NSCLC.
- Epigenetic silencing via promoter hypermethylation is the primary mechanism for Foxa2 downregulation.
- Foxa2 and other airway transcription factors represent potential therapeutic targets in lung cancer pathogenesis.
Related Concept Videos
01:37Epigenetic Regulation
X-chromosome...
01:46Epigenetic Regulation
01:46Epigenetic Regulation
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
02:23Abnormal Proliferation