Epigenetics and colorectal cancer pathogenesis

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.

Figure 1

A simplified model of DNA methylation-mediated gene silencing. (A). Methylation of the cytosine of the CpG dinucleotides in a gene promoter region within a transcription factor’s binding consensus sequence motif may be recognized by the transcription factor (TF) as a “mutation” and thus results in loss of TF binding and transcription initiation. (B). Methyl-CpGs may recruit MBD protein binding to the methylated DNA region in a gene promoter region. The MBD proteins may physically block TF binding to the promoter region or recruit repressors to inhibit TF activity, and thereby silencing gene transcription.

Figure 2

The crosstalk network between the DNA methylation and histone modification systems in the context of gene transcription initiation in CRC cells. DNMTs directly catalyze CpG methylation, whereas HAT and HDAC, as well as HDM and HMTase, antagonize each other to determine specific acetylation and methylation of specific histone residues. However, DNMT, HAT, HDAC, HMTase, and HDM may directly interact with each other while associated with chromation in a gene promoter region. These specific epigenetic modifications of DNA and histone, in concert with specific protein-protein physical interactions between these epigenetic modification enzymes, define a transcriptionally repressive chromatin conformation to block/inhibit transcription factor (TF)-dependent transcription initiation by RNA polymerase (RNA Pol II).

Figure 3

A “one-two punch” strategy of combined chemotherapy and immunotherapy to suppress metastatic human CRC. The apoptotic-resistant CRC cells are first targeted with apoptosis-sensitizing epigenetic drug(s) (e.g., decitabine and vorinostat) to sensitize the tumor cells to apoptosis. Once “sensitized”, patients are then treated with immune effector molecules or FasL⁺ tumor-specific CTLs that promote apoptosis to effectively destruct the tumors.