Integrated analysis using methylation and gene expression microarrays reveals PDE4C as a prognostic biomarker in human glioma.

Hypermethylation of tumor suppressor promoters is generally accepted to indicate poor prognosis in glioma; however, the DNA methylation patterns associated with different glioma prognoses remain to be elucidated. In the present study, promoter methylation and gene expression microarrays were used to screen candidate genes between different grades of glioma. Survival analysis was performed using the Kaplan‑Meier (KM) method. Promoter methylation and protein expression of phosphodiesterase 4C (PDE4C) was examined in different grade gliomas and the correlation between PDE4C and wild-type (WT) p53 was evaluated in glioma cell lines. In addition, gene ontology and gene set variation analysis were used to examine PDE4C function. We found PDE4C exhibited promoter hypermethylation in high-grade glioma samples and hypomethylation in low-grade glioma, with PDE4C expression levels showing the reverse. This indicated PDE4C may be a candidate glioma biomarker. Through studies of PDE4C methylation and expression status in an independent cohort of 124 patient samples (56 low-grade and 63 high-grade glioma and 5 normal brain), we identified PDE4C as having significant promoter methylation and lower expression in high-grade glioma. Hypermethylation and reduced PDE4C protein expression were associated with grade progression and overall survival. In glioma cell lines, PDE4C was upregulated by demethylation treatment with 5-Aza-2'-deoxycytidine and WT p53 expression was downregulated after PDE4C siRNA suppression. Finally, we found PDE4C promoted apoptosis and inhibited migration in a U87 cell line. On the basis of these observations and the results from subset analysis, it is reasonable to conclude that PDE4C may function as a tumor suppressor by promoting apoptosis through the WT p53 pathway and inhibiting cell migration. The data show that PDE4C is downregulated through promoter hypermethylation in glioma.