Changes in transcriptional factor binding capacity resulting from promoter region methylation induce aberrantly high GDNF expression in human glioma.

Glial cell line-derived neurotrophic factor (GDNF), which belongs to transforming growth factor β superfamily, plays important roles in glioma pathogenesis. Gdnf mRNA is aberrantly increased in glioma cells, but the underlying transcription mechanism is unclear. Here, we found that although the base sequence in the promoter region of the gdnf gene was unchanged in glioma cells, there were significant changes in the methylation level of promoter region I (P < 0.05) in both high- and low-grade glioma tissues. However, the methylation degree in promoter region II was notably decreased in low-grade glioma tissue compared to normal brain tissue (P < 0.05), and the demethylation sites were mainly located in the enhancer region. Conversely, methylation was markedly increased in high-grade glioma tissue (P < 0.05), and the sites with decreased methylation level were mainly located in the silencer region. The binding capacities of several transcriptional factors, such as activating protein 2, specificity protein 1, ETS-related gene 2, and cAMP response element binding protein, which specifically bind to regions with altered methylation status decreased along with the pathological grade of glioma, and the differences between high-grade glioma and normal brain tissue were significant (P < 0.05). The results suggest that changes in transcriptional factor binding capacity are due to changes in promoter region methylation and might be the underlying mechanism for aberrantly high gdnf expression in glioma.