Abstract
Epigenetic mechanisms have important roles in carcinogenesis. We certified that the mRNA translation-related gene cytoplasmic polyadenylation element-binding protein 1 (CPEB1) is hypomethylated and overexpressed in glioma cells and tissues. The knockdown of CPEB1 reduced cell senescence by regulating the expression or distribution of p53 in glioma cells. CPEB1 is also regulated directly by the tumor suppressor miR-101, a potential marker of glioma. It is known that the histone methyltransferase enhancer of zeste homolog 2 (EZH2) and embryonic ectoderm development (EED) are direct targets of miR-101. We demonstrated that miR-101 downregulated the expression of CPEB1 through reversing the methylation status of the CPEB1 promoter by regulating the presence on the promoter of the methylation-related histones H3K4me2, H3K27me3, H3K9me3 and H4K20me3. The epigenetic regulation of H3K27me3 on CPEB1 promoter is mediated by EZH2 and EED. EZH2 has a role in the regulation of H3K4me2. Furthermore, the downregulation of CPEB1 induced senescence in a p53-dependent manner.
Highlights
In our previous research study, the DNA methylome in glioma was constructed by high-throughput methylated DNA IP combined with the use of a promoter and CpG islands microarray
The correlation between CPEB protein 1 (CPEB1) expression, methylation status and overall survival (OS) was statistically significant (Figures 1f and g). These results suggest that CPEB1 overexpression and hypomethylation may be involved in glioma carcinogenesis
Using the Kaplan–Meier method, we found that the glioma patients who harbored the overexpression or hypomethylation of CPEB1 had poor outcomes
Summary
In our previous research study, the DNA methylome in glioma was constructed by high-throughput methylated DNA IP combined with the use of a promoter and CpG islands microarray. Cytoplasmic polyadenylation element-binding (CPEB) protein is the key factor that controls mRNA translation. CPEB binds the cytoplasmic polyadenylation element in the 30-UTRs of responsive mRNAs.[12] In Xenopus oocytes and early-stage embryos, CPEB protein 1 (CPEB1) is a dual-function protein. In response to developmental cues or stimulation, CPEB1 dissociates from the repression complex and activates translation.[13] Recent data have demonstrated a correlation between CPEB1 and senescence.[14] Sasayama T et al[15] examined CPEB1 mRNA levels in several tumor cell lines, such as hepatoma, glioma, lung cancer, colon cancer and pancreatic cancer, and demonstrated that 50% of these cell lines had high expression levels of CPEB1. We confirmed the promoter methylation status and the expression of CPEB1 in glioma cell lines and tissues and elucidated the phenotype and mechanism of CPEB1 dysregulation
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