Epigenetic Methylation and Colorectal Cancer
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One of the many questions you might ask yourself when diagnosed with colorectal cancer is, how? Unlike some other cancers, colorectal cancer is incredibly heterogenous, and rarely is it ever a case that it develops solely through a singular change in your body. It takes an accumulation of alterations, both genetic and epigenetic, over a significant period of time before the cancer forms.
Of the different possible epigenetic modifications, the significance of epigenetic methylation in the development and progression of colorectal cancer cannot be understated. Not only is it an important colorectal cancer biomarker, but it is also a potential treatment target, and may come up in discussion with your doctors.
This overview will give you a broad understanding of one of the most well studied epigenetic modifications that also plays a significant role in colorectal cancer development and progression.
What is epigenetic methylation?
Epigenetic methylation refers to the modification of the DNA molecule by the addition of a methyl group to certain regions of the genome. This process can lead to the silencing of important genes involved in the regulation of cell growth and differentiation, thereby promoting the development and progression of colorectal cancer.
The development of colorectal cancer is a multistep process that involves the accumulation of genetic and epigenetic alterations. While genetic changes refer to alterations in the DNA sequence, epigenetic changes refer to changes in the way the DNA is read and interpreted, without altering its sequence.
Epigenetic methylation is a reversible process and involves the addition of a methyl group to the carbon-5 position of the cytosine ring of the DNA molecule. This modification results in the silencing of gene expression, which can lead to the activation of oncogenes and the inactivation of tumor suppressor genes.
Gene silencing and gene regulation
`Several studies have demonstrated that DNA methylation is involved in the regulation of important genes that play a role in the development and progression of colorectal cancer.
For example, the APC (adenomatous polyposis coli) gene, which is commonly mutated in familial adenomatous polyposis (a hereditary precursor condition to colorectal cancer), has been shown to be epigenetically silenced in many colorectal cancer cases. Given that the APC protein encoded by the gene acts as a tumor suppressor, silencing the APC gene results in uncontrolled cellular growth that manifests in the form of hundreds to thousands of polyps forming in the colon, the hallmark characteristic of familial adenomatous polyposis.
Other genes that have been implicated in the development and progression of colorectal cancer and are regulated by DNA methylation include p16INK4A and MLH1.
Gene | Role | Effects of epigenetic methylation |
|---|---|---|
APC | Encodes the adenomatous polyposis coli (APC) protein which controls how often a cell divides, how it attaches to other cells within a tissue, and whether a cell moves within or away from a tissue | Gene silencing, resulting in uncontrolled cell growth |
p16INK4A | Encodes the p16INK4A protein which acts as a tumor suppressor by slowing cell division | Gene silencing, promoting cell division |
MLH1 | Encodes the MLH1 protein, a component of the DNA mismatch repair system | Gene silencing, promoting unrepaired errors in the DNA |
In addition to gene silencing, DNA methylation has also been shown to play a role in the regulation of microRNAs (miRNAs), which are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level — a stage that occurs right before the proteins are formed based.
The expression of miRNA is often regulated by DNA methylation, and miRNAs have been shown to play a critical role in the development and progression of colorectal cancer. For example, microRNA-29b is a tumor suppressor miRNA that plays critical roles in cancer at all stages, including onset and metastasis. It promotes apoptosis — or programmed cell death — in tumor cells and prevents cells from losing the polarity and cell-cell adhesion, thereby preventing cell migration and metastasis. microRNA-29b has been shown to be downregulated in colorectal cancer due to DNA methylation, and its restoration has been shown to re-induce apoptosis in cancer cells.
Potential diagnostic and treatment target
As it stands, epigenetic methylation is a useful biomarker for colorectal cancer diagnosis, with two methylation-based diagnostic biomarkers already approved for colorectal cancer — SEPT9 and the combination of NDRG4 and BMP3, the biomarkers central to the Epi proColon® and Cologuard® diagnostic kits respectively. New biomarkers are similarly being reviewed based on different sample sources such as blood, stool, urine and tumor tissue. Besides aiding in diagnostics, these new biomarkers are also being studied as ways to measure tumor burden, disease recurrence, and estimate disease prognosis.
The use of epigenetic drugs that target DNA methylation is also a promising strategy for the treatment of colorectal cancer. These drugs work by inhibiting the activity of DNA methyltransferases, which are enzymes that add methyl groups to the DNA molecule.
Several drugs that target DNA methylation have been developed and are currently in clinical trials for the treatment of colorectal cancer, including azacitidine and decitabine that inhibit DNA methylation. By inhibiting DNA methylation, these drugs can restore the expression of important genes that are silenced in cancer cells.
