Detailed analysis of expression and promoter methylation status of apoptosis-related genes in prostate cancer

Abstract

Apoptosis is known to be involved in tumorigenesis and a defective ratio between cell proliferation and apoptosis may contribute to the emergence of a malignant phenotype. Transcriptional silencing of apoptosis-related genes associated with aberrant promoter methylation may impair the apoptotic machinery, ultimately leading to cancer development. Aberrant promoter methylation of numerous genes involved in many different pathways is frequent in prostate cancer. Our aim was to quantitatively assess the methylation status of several apoptosis-related genes in prostate adenocarcinoma (PCa) and its precursor lesion, high-grade prostatic intraepithelial neoplasia (HGPIN). First, 120 PCa and 39 HGPIN were screened for altered expression of BCL2, CASP8, CASP3, DAPK DR3, DR4, DR6, FAS, TMS1, TNFR2, using 28 benign prostate hyperplasias and 10 normal prostates as controls. Underexpressed genes were then assessed by quantitative methylation-specific PCR to determine the promoter methylation status. Finally, quantitative mRNA expression of aberrantly methylated genes was performed and methylation data was correlated with standard clinicopathologic parameters. DAPK, DR4 and TNFR2 were significantly overexpressed in HGPIN and PCa, whereas BCL2, TMS1, and FAS were downregulated. Although methylation levels were significantly higher for TMS1 and BCL2 (correlating with advanced stage), an inverse correlation with mRNA expression was found only for BCL2. We concluded that the apoptotic pathways are largely preserved in prostate carcinogenesis, in particular the extrinsic pathway, with the exception of FAS and TMS1, which are epigenetically downregulated. In addition, BCL2 was also found to be frequently silenced in PCa due to aberrant promoter methylation, thus supporting a future role for apoptosis-targeted therapy in prostate cancer.

DNA methylation in neonates born to women receiving psychiatric care

“…25,26,29 Alterations in TNFRSF21 methylation or gene expression influence complex traits ranging from learning and memory and emotional responses to stressful events to cancer. 30,31 CHRNA2 is a broadly-expressed subunit of nicotinic acetylcholine receptors. 32 In addition to its role in nicotine dependence and neurocognitive functioning, 33,34 CHRNA2 is located in a region of chromosome 8p that is suggested to contribute to psychiatric and neurodegenerative disorders.…”

Anti-neoplastic properties of hydralazine in prostate cancer

“…Alterations in DNA methylation are early events in human carcinogenesis, including PCa, which are conserved during cancer progression [4]. Aberrant methylation of CpG dinucleotides in gene promoter regions is associated with transcriptional repression, not only of tumor-suppressor genes, but also of genes with important regulatory functions [5, 6]. DNA methyltransferases (DNMTs) are a group of enzymes responsible for the establishment and maintenance of methylation patterns.…”

DAPk and pyruvate kinase: Unlikely partners in cancer metabolic regulation

“…Notably, there are several examples in the literature of cancers and virally transformed cells where both conditions have been met. 3,[9][10][11] These examples support the possibility that DAPk has a dual function in tumor suppression by inducing cell death and independantly slowing down cell proliferation through activation of pyruvate kinase. Further study on the metabolic profile of the cancers in which DAPk expression is maintained could possibly explain the selective advantage of DAPk upregulation.…”