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PDCD4 gene silencing in gliomas is associated with 5'CpG island methylation and unfavourable prognosis
Fei Gao1, Xiaoyan Wang, Faliang Zhu
1Department of Immunology, School of Medicine, Shandong University, Jinan, Shandong, China.
Abstract:
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.
Insights
Programmed cell death 4 (PDCD4) gene silencing in gliomas is primarily caused by 5'CpG island methylation. Reactivating PDCD4 expression may offer a new therapeutic strategy for brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Programmed cell death 4 (PDCD4) is a tumor suppressor inhibiting oncogenesis.
- Loss of PDCD4 expression is observed in various cancers, including gliomas.
- Mechanisms of PDCD4 gene silencing in gliomas are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms of PDCD4 gene silencing in gliomas.
- To determine the role of PDCD4 methylation in glioma development and prognosis.
- To explore PDCD4 reactivation as a potential therapeutic strategy for gliomas.
Main Methods:
- Analysis of 5'CpG island methylation in glioma tissues.
- Correlation of PDCD4 methylation with PDCD4 mRNA expression.
- Treatment of glioma cells with a DNA methyltransferase inhibitor (5-aza-2'-deoxycytidine).
- Assessment of cell proliferation and colony formation.
- Longitudinal study of glioma patient prognosis.
Main Results:
- 5'CpG island methylation was identified as the predominant cause of PDCD4 mRNA silencing in 47% of glioma tissues.
- PDCD4 methylation significantly correlated with loss of PDCD4 mRNA expression.
- Inhibition of methylation restored PDCD4 expression, reduced glioma cell proliferation, and colony formation.
- Loss of PDCD4 expression was associated with poor prognosis in high-grade glioma patients.
Conclusions:
- PDCD4 5'CpG island methylation silences PDCD4 expression at the mRNA level in gliomas.
- PDCD4 reactivation presents a potential novel therapeutic approach for glioma treatment.
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