Abstract
Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.
Highlights
Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway
Other epigenetic mechanisms, including nucleosomal occupancy and remodeling, chromatin looping, and noncoding RNAs, plays important roles in CRC development [18], the major epigenetic mechanisms which are believed to play a crucial role in cancer development includes DNA methylation of cytosine bases in CpG dinucleotides and post-translational modifications of histone proteins that mediate the packaging of DNA into chromatin and regulate gene expression through controlling chromatin conformation [77]
The multimeric Polycomb group (PcG) repressive complexes (PRCs), mainly PRC1 and PRC2, can silence gene expression either independently or synergistically, components of the PcG protein complex interact with DNA methyltransferases (DNMTs), and are directly involved in DNMT-dependent DNA hypermethylation in vivo [115]. These PcG protein complexes are thought to serve as a recruitment platform for DNMTs [116]. Both PRC1 and PRC2 proteins interact with DNMT1 and DNMT3b, establishing a potential key role for these proteins in catalyzing methylation-associated transcriptional silencing of target genes in cancer cells [116,117,118]
Summary
Cancer is a term used for a disease in which abnormal cells in the human body start dividing and growing without control and are capable of invading other tissues through the blood and lymphatic system, a phenomenon known as metastasis. Serrated polyps are associated with microsatellite instability (MSI) and aberrant DNA hypermethylation, whereas tubular adenomas more commonly arise via inactivation of the APC tumor suppressor gene and concurrent genetic alterations resulting from chromosomal instability [14]. What further complicates this issue is the recent technology advances that reveal that thousands of molecular alterations exist in the average CRC genome but it is widely believed that only a subset of these alterations drive the cellular and clinical behavior of CRC development. In addition to DNA hypermethylation that often occurs in the promoter region of tumor suppressor genes, epigenetic regulation of CRC epigenome includes post-translational histone modifications, primarily histone acetylation and methylation that play critical roles in regulation of expression of oncogenes and tumor suppressor genes
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