What is it about?
Our research highlight the potential of allele-specific CpG/CCWGG methylation profiling of the PSA promoter as a valuable tool in improving the PSA-based prostate cancer diagnostics. These new methylation patterns may also help differ cancer subtypes.
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Why is it important?
Allele-specific PSA promoter methylation has a unique allelic methylation pattern and can be used to distinguish cancer from non-cancerous diseases. Focusing on both CpG and CCWGG sites, we characterize methylation signatures across prostate-derived cell lines: PC3 cells (androgen-independent PCa) display biallelic CpG and loss proximal (CCWGG)2 methylation, associated with transcriptional silencing of PSA. LNCaP cells (androgen-sensitive PCa) lack promoter methylation entirely, supporting biallelic PSA expression. BPH1 cells (benign hyperplasia) exhibit monoallelic CpG/CCWGG methylation, correlating with the lack of PSA expression. It is safe to say that the uniqueness of the allelic CpG/CCWG methylation pattern has great potential as a translational biomarker for distinguishing cancer from non-cancerous diseases (Fig. 1). The finding that unmethylated PSA promoter is consistent with prostate cancer represents a new paradigm for DNA methylation as a cancer-specific biomarker. It is known that low PSA levels do not necessarily exclude PCa. Our findings suggest that the detection of biallelic methylation may indicate an aggressive form of prostate cancer. The identification of CCWGG methylation—a motif typically associated with prokaryotic methyltransferases—as a potential regulator of allele-specific expression in mammalian cells is particularly novel.
Perspectives
Our work opens a framework for investigating non-CpG methylation in gene regulation, epigenetic memory and cancer biology. Future studies should aim to validate these findings in clinical cohorts, determining the impact of CCWGG methylation on PSA expression in mammalian cells. Our discovery of monoallelic CpG/CCWGG methylation suggests a novel functionality of CCWGG methylation associated with signaling for monoallelic methylation and gene expression. If PSA expression is allele-methylation dependent and its expression in normal prostate regulated by imprinting and is monoallelic, then both PC3 and LNCaP cases could be considered as loss of imprinting (LOI), which is known to be associated with the pathological condition.
Mikhail Baryshev
Read the Original
This page is a summary of: Allele-specific methylation of the PSA promoter in prostate cells: A new translational marker for the differential diagnosis of prostate cancer, Genes & Diseases, May 2025, Tsinghua University Press,
DOI: 10.1016/j.gendis.2024.101487.
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