PDCD4 gene silencing in gliomas is associated with 5′CpG island methylation and unfavourable prognosis

Programmed cell death 4 (PDCD4) is a newly described tumour suppressor that inhibits oncogenesis by suppressing gene transcription and translation. Loss of PDCD4 expression has been found in several types of human cancers including the most common cancer of the brain, the gliomas. However, the molecular mechanisms responsible for PDCD4 gene silencing in tumour cells remain unclear. Here we report the identification of 5'CpG island methylation as the predominant cause of PDCD4 mRNA silencing in gliomas. The methylation of the PDCD4 5'CpG island was found in 47% (14/30) of glioma tissues, which was significantly associated with the loss of PDCD4 mRNA expression (gamma=-1.000, P < 0.0001). Blocking methylation in glioma cells using a DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the PDCD4 gene expression, inhibited their proliferation and reduced their colony formation capacity. Longitudinal studies of a cohort of 84 patients with gliomas revealed that poor prognosis of patients with high-grade tumours were significantly associated with loss of PDCD4 expression. Thus, our current study suggests, for the first time, that PDCD4 5'CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. These results also indicate that PDCD4 reactivation might be an effective new strategy for the treatment of gliomas.