Abstract
Our previous report identified PR domain containing 16 (PRDM16), a member of the PR-domain gene family, as a new methylation associated gene in astrocytoma cells. This previous study also reported that miR-101 is a tumor suppressor in glioma. The present study confirms that PRDM16 is a hypomethylated gene that can be overexpressed in astrocytoma patients and demonstrates that the hypomethylation status of the PRDM16 promoter can predict poor prognoses for astrocytoma patients. The results reported herein show that PRDM16 was inhibited by miR-101 directly and also through epigenetic regulation. PRDM16 was confirmed as a new target of miR-101 and shown to be directly inhibited by miR-101. miR-101 also decreased the expression of PRDM16 by altering the methylation status of the PRDM16 promoter. miR-101 was associated with a decrease in the methylation-related histones H3K4me2 and H3K27me3 and an increase in H3K9me3 and H4K20me3 on the PRDM16 promoter. In addition, EZH2, EED and DNMT3A were identified as direct targets of miR-101, and miR-101 suppressed PRDM16 expression by targeting DNMT3A which decreases histone H3K27me3 and H3K4me2 at the PRDM16 core promoter. The results reported here demonstrate that miR-101 disrupted cellular mitochondrial function and induced cellular apoptosis via the mitochondrial pathway; for example, MMP and ATP levels decreased, while there was an increase in ADP/ATP ratios and ROS levels, levels of cleaved Caspase-9 and cleaved-PARP, the Bax/Bcl-2 ratios, and Smac release from the mitochondria to the cytoplasm. Knockdown of PRDM16 reversed the anti-apoptotic effect of miR-101 inhibition. In summary, miR-101 reversed the hypomethylation of the PRDM16 promoter which suppressed the expression of PRDM16, disrupted cellular mitochondrial function, and induced cellular apoptosis.
Highlights
PRDM16 (PR domain containing 16) is a member of the PR-domain gene family
PRDM16 protein levels were amplified in astrocytoma cell lines (Figure 1E) and in 39 of 50 astrocytoma tissues
The results revealed that lower PRDM16 expression or methylated PRDM16 correlated with higher survival rate, whereas PRDM16 hypomethylation or higher PRDM16 expression levels correlated with a lower survival rate (Figure 1G and 1H)
Summary
PRDM16 (PR domain containing 16) is a member of the PR-domain gene family. The proteins encoded by these genes are a type of zinc finger transcription factor and contain N-terminal PR domains [1]. This protein family is involved in the transduction of signals that control cell proliferation, differentiation and apoptosis [2, 3, 4]. In AMLNK patients, PRDM16 has a high level of expression due to promoter hypomethylation [12]. The data indicated that the promoter of PRDM16 was hypomethylated. These results have yet to be validated
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