WOMEN IN CANCER THEMATIC REVIEW: Diverse functions of DNA methylation: implications for prostate cancer and beyond

Abstract

Prostate cancer is one of the most common malignancies in men worldwide. Current clinical screening ensures that most prostate cancers are diagnosed while still organ confined, but disease outcome is highly variable. Thus, a better understanding of the molecular features contributing to prostate cancer aggressiveness is being sought. For many cancers, aberrant genome-wide patterns of cytosine DNA methylation in CpG dinucleotides distinguish tumor from normal tissue and contribute to disease progression by altering the transcriptome. In prostate cancer, recent genomic studies identified cancer and high grade-specific differential DNA methylation in gene promoters, gene bodies, gene 3′ ends and at distal regulatory elements. Using examples from developmental and disease systems, we will discuss how DNA methylation in each of these genomic contexts can contribute to transcriptome diversity by modulating transcription initiation, alternative transcription start site selection, alternative pre-mRNA splicing and alternative polyadenylation. Alternative transcripts from the same gene often exhibit altered protein-coding potential, translatability, stability and/or localization. All of these can have functional consequences in cells. In future work, it will be important to determine if DNA methylation abnormalities in prostate cancer modify the transcriptome through some or all of these mechanisms and if these DNA methylation-mediated transcriptome alterations impact prostate tumorigenesis and aggressiveness.

DNA Methylation Regulates Alternative Polyadenylation via CTCF and the Cohesin Complex

“…Finally, it is important to note that DNA methylation-regulated APA may not be restricted to the 546 candidates we uncovered using the HCT116/DKO comparison since these cells do not capture tissue-and cell type-specific DNA methylation patterns that exist. This complexity in genome organization, epigenetic variation, and alternative poly(A) site usage highlights an intersection between epigenetic regulation and transcriptome diversity that warrants further studies (Sweet and Ting, 2016).…”

Integrated analysis to identify the AC005154.6/hsa-miR-29c-3p/CCNL2 axis as a novel prognostic biomarker associated with immune infiltration in prostate cancer

“…Tumors often exhibit abnormal patterns of cytosine DNA methylation in CpG dinucleotides, which contribute to disease progression. In prostate cancer, a high grade-specific difference in DNA methylation has been observed in gene promoters, gene bodies, and gene 3' ends [ 44 ]. In this study, we found that DNA methyltransferases were highly expressed in the CCNL2 high group.…”

DNA Methylation-Based Testing in Liquid Biopsies as Detection and Prognostic Biomarkers for the Four Major Cancer Types

“…Typically, this process occurs on cytosine residues present at CpG dinucleotides commonly found in large clusters named CpG islands, which are predominantly located at the 5′ end of genes, occupying approximately 60% of human gene promoter regions [20,23,24]. Although gene promoter hypermethylation is associated with transcription repression of the nearby gene ( Figure 4), depending on DNA methylation genomic location, it can display different functions [22,25]. Epigenetic gene silencing by DNA promoter methylation may occur either directly, by blocking transcription factors to prevent binding to target sites in or near the promoter, or indirectly, through binding of methyl-CpG-binding proteins (MBP), which can recruit other enzymes like DNMTs and histone deacetylases (HDAC), leading to chromatin conformation changes that further repress gene transcription [20,22].…”