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Apoptosis, also known as programmed cell death, plays an essential role in eliminating excessive, damaged or harmful cells. Previous work has demonstrated that anticancer drugs induce cell apoptosis by inducing cytotoxicity. In recent years, several reports demonstrated modulated expression of DNA methyltransferases 1 (DNMT1) and acetylcholinesterase (AChE) in a variety of tumors. In this study, we showed that the expression of DNMT1 was decreased and the methylation of CpGs in the promoter of AChE was reduced in anticancer drugs-induced apoptotic hepatocellular carcinoma cells. Silencing of DNMT1 expression by AZA or RNA interference (RNAi) restored AChE production and inhibition of AChE expression by RNAi protected HCC cells from anticancer drugs-induced apoptosis. Furthermore, we demonstrated that the regulation of AChE by DNMT1 was involved in the phosphorylated p38 pathway in anticancer drugs-induced apoptosis. In addition, immunohistochemical staining showed that P-p38, DNMT1 and AChE were aberrantly expressed in a subset of HCC tumors. Taken together, we demonstrated the regulation of AChE by DNMT1 and further, we found that this regulation was involved in the phosphorylated p38 pathway in anticancer drugs-induced apoptosis.

In recent years, widespread antisense transcripts have been identified systematically in mammalian cells and are known to regulate gene expression, although their functional significance remains largely unknown. Previous work has identified that acetylcholinesterase (AChE) is expressed aberrantly in various malignant tumors and function as a tumor growth suppressor. However, the mechanism of AChE gene regulation in tumors remains unclear. In this study, we show that the AChE antisense RNA (AChE-AS) play an important role in AChE expression regulation. An inverse relationship was identified between AChE-AS and AChE expression in hepatocellular carcinoma and hepatoma cells. The silenced AChE-AS corresponds to elevated expression of AChE. Furthermore, we demonstrated that reduced AChE-AS increased H3K4 methylation and decreased H3K9 methylation in the AChE promoter region. As expected, elevated AChE levels induced by inhibition of AChE-AS enhanced anticarcinogen-induced apoptosis. These observations demonstrated that AChE-AS modulates AChE expression and exerts an anti-apoptotic effect through direct repression of AChE expression in HCC cells. Thus, natural antisense RNA may play an important role in AChE regulation via affecting the epigenetic modification in the AChE promoter region.

The apoptosis pathway has been proposed to be involved in causing neuronal cell death in the pathogenesis of Parkinson's disease. However, the details of this pathway are poorly understood. Previous research has shown increased acetylcholinesterase expression during apoptosis in various cell types, which suggests that acetylcholinesterase has a potential role in neuronal cell death. In this study, we found that acetylcholinesterase protein expression increased and caspase-3 was activated in PC12 cells treated with 1-methyl-4-phenylpyridinium. Furthermore, the genetic or pharmacological inhibition of acetylcholinesterase was shown to protect PC12 cells from MPP+ induced apoptotic cell death. To study the function of acetylcholinesterase as a mechanism of neuronal cell death in vivo, we subsequently established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinson's disease mouse model utilizing acetylcholinesterase-deficient mice. Studies in these mice revealed reduced dopaminergic neuron loss and lower expression levels of apoptotic proteins in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated heterozygous mice compared to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated wild-type mice. We conclude that it is highly probable that acetylcholinesterase is involved in the pathogenesis of the neurotoxin model of Parkinson's disease via apoptosis. Specifically, a deficiency or inhibition of acetylcholinesterase can decrease apoptosis and protect dopaminergic neurons in the neurotoxin model of Parkinson's disease.