The epigenetic contribution to understanding of cancer development: undergraduate essay

Epigenetics is the study of genetically heritable changes, changes that do not originate from the basic underlay of the DNA. These changes do not affect the basic sequence of nucleotides in the DNA, but they play a major role in the activation and inactivation of DNA. The major epigenetic activities in the cell are DNA methylation, histone modification, and microRNA (miRNA) (Esteller, 2005). This study will seek to establish how DNA methylation, histone modifications and miRNA contribute to the development of cancerous cells.

Cancer is a result of interplay between genetic and epigenetic factors. There has been intensive research to identify mutations accompanied by cancer. This type of research has shown the genetic mutations that happen in inheritable cancer cases. In addition, mutations that occur in the event of common cancers have been also identified. Tumor development is a common feature in the majority of cancer cases, but only a limited number of tumorigenesis cases have been linked with genetic mutations. According to Esteller (2005), this means epigenetic changes are contributory to the process.

In a normal cell, DNA methylation is used control gene activity and the setup of the nucleus in the cell. In a strand, methylation will occur in cytosines that are before guanines (CpG). Majority of these are near the 5’ end of the strand, hence 5’ capping is referred to as methylation (Lund & van Lohuizen, 2004). Methylation controls the functioning of tissue specific gene segments. DNA methylation takes place in the presence of chemical modifications achieved through histone proteins. Methylation process is controlled by DNA methyltransferase enzyme (DNAMTs). Epigenetic events can also take part in genesis of cancer. According to Lund & van Lohuizen (2004), epigenetic events can also be involved directly in the initiation of cancer.

To understand DNA methylation better, a study is done between normal cells and timorous cells. In timorous cells, the “standard” architecture of the CpG methylation is inverted. This means, CpG islands that precede tumor suppressor gene promoters become hypermethylated and methylation of oncogenic promoter sequences as well as repeat sequences is reduced. The result is, hypermethylation of these sequences results to them being silences and can no longer transcribe. This is an epigenetic event and it is highly dangerous. The effect is cell reproduction and growth occurred uncontrollably (De Carvalho, 2012). The physical effect is tumorigenesis, one of the symptoms of cancer syndromes. Some of the genes silenced as a result of hypermethylation include; cell-cycle inhibitors, DNA repair, cell cycle regulator, and many others.

On the other hand, hypomethylation of the CpG dinucleotides in other sections of the strand result to loss of DNA reactivation of transposable elements and imprinting capabilities. The result of this effect is chromosome instability. Specifically, loss of imprinting capabilities like that of insulin-like growth factor (IGF2) gene increases the probability of colorectal cancer especially in newborns.

Epigenetic events do not affect the sequence of the DNA strand. They can also be the result of a number of factors. It is therefore possible for DNA mutation to cause cellular changes, but epigenetic changes because of the mutation result to metastasis capabilities of the transformed cell. This would therefore mean, genetic mutation can cause cancer, but the development of cancer is solely the work of epigenetic events. This condition could then be furthered by continued DNA changes, which promote advance epigenetic changes.

Once cancer sets in, epigenetic events play a role in maintain and drive it. Cancerous cells have genomes with very low methylcystosine compared to the genome of a normal cell. Statistically, cancerous cells have 20-50% reduction in methylation at CpG dinucleotides in the strand (Lund & van Lohuizen, 2004). The hypomethylation situation that is a result of DNMTs can result to mitotic recombination as well as rearrangement of the chromosome. The result of these events is aneuploidy, which is caused by inability of chromosomes to “normally” separate during mitosis.

In normal cells, CpG island methylation plays a major role in regulation of gene expression. However, cytosine methylation can directly cause genetic mutations that are a perfect precursor for cancer. Cytosine methylation forms a suitable state for hydrolysis of amine group and thymine conversion, which can result to change of chromatic proteins. In addition, cytosine methylation affect the amount of UV light absorbable to the nucleotide resulting to formation of pyrimidine dimmers. In case of mutation changes that cause loss of heterozygosity at a tumor suppressor gene site, these genes can be inactivated resulting to prolific cell growth.

In the recent past, histone has been known to be a packaging material only, but it is now evident that histone has molecular properties that participate in regulation of gene expression. Based on recent research results, it is clear that DNA methylation and histone modifications play a role in physiology of cells and tissues (De Carvalho, 2012).

Histone modification has been documented to have three main post translation modifications. These are methylation, phosphorylation and acetylation (Fraga, 2005). For each of these processes, there are enzymes, which have the responsibility of aligning the right marker for transcription as well as removing it. Active segments of genetic strands have particular elements in abundance while the inactive counterparts also have some elements in high concentration. These elements respectively include H3K4me3 and H3K9me3 (Esteller & Herman, 2004). However, there is no standard rule guiding active and inactive DNA segments, the result is; histones from these different sections have similar modification, which affect gene activity. This means, risks of oncogenic events are eminent.

Histone acetylation has the role of opening up the structure of chromatin. This role is controlled by enzymes that include; histone acetyltransfarase (HATs) that activate transcription and histone deacetylases (HDACs) that are replace transcription. In the event of cancer appropriate conditions, several HAT genes are modified in a number of ways depending on the type of cancer. For example, p300 HAT gene undergoes mutation in case of gastrointestinal related tumors (Lund & van Lohuizen, 2004). On the contrary, mutational changes in HDAC are not common.  This means, in case of a cancer event affecting HAT, transcription will take place but repressor HDAC won’t. The result for is super activity in the role of the transcribed gene. If it was a growth gene, it will result to excess production of cells, hence tumorigenesis. However, this occurrence is responding well to anti-cancer drugs.

In histone methylation, normally, all lysine methyltransferases targeting histone N-terminal have a “SET domain”. This domain has lysine methyltransferase activity and it has been shown that many proteins that contain SET domains have highly susceptible to cancer. An example of such a protein is the family of Suv39 enzymes that is responsible for the catalysis of H3K9. One of the cancers that these enzymes are highly susceptible to is the B cell lymphomas.

The third histone activity liked to cancer epigenetic is phosphorylation. Cancer has been linked to the misregulation of H3S28 as well as H3S10. The misregulation event occurs during mitosis. This misregulation is because of malfunctioning of Aurora Kinases that linked to cancer and are responsible for phosphorylation of H3.

In general, the different histone modifications function in a sequential manner to control several cell processes among them repair, replication and transcription. Changes in the histone modification setups are considered to interfere with the levels and styles of histone marks, which cause misregulation of chromosome processes. This misregulation forms the suitable conditions and increases the chances for cancer development.

The third epigenetic factor attributed to cancer development is the role of microRNA. miRNA has a major role in DNA transcription. In mammals, is controls approximately 60% of transcriptional activities of genes encoding for proteins. The first well-known miRNA to be reported was the deletion on chromosome 13 in chronic lymphocytic leukemia (Lund & van Lohuizen, 2004). Studies showed that two miRNA genes are responsible mir-15 and mir-16. These are located in the strand segment that is deleted in this case. This study was used to suggest that; miRNA had a major role in some of the diseases, which remained abstract.

In the event of cancer syndrome, some of these have been shown to undergo methylation, which results to silencing. The natural intent of methylation of cellular elements is to take them into an inactive state. An example of miRNA silencing in cancer cells has been documented is Let-7 and mir-15/16 which has the role of down-regulating BCL2 and RAS oncogenes. Another example of the silencing of mir-125b1, which acts as tumor suppressor, has been documented in prostate cancer cells (De Carvalho, 2012).

For the majority of human cancer, RAS oncogene mutations are present. In fact, statistics show that the exact number is 15-30% of all human cancers. For example, over expression of RAS oncogene is a common symptom for lung cancer, according to Mattick & Makunin (2005), this has been attributed to malfunctioning of Let-7 miRNA. The exact physical result of reduced expression of let-7 is excessive cell growth, which results to tumorigenesis. Currently, miRNA profiling is used to characterize different cancer types.

Knowledge of epigenetic as far as cancer is related is proving highly advantageous. Epigenetic attributes are being used as treatment or cancer therapeutic strategies. The good thing about epigenetic changes is that, unlike genetic changes, they are reversible. Molecular inhibitors are being developed to counter histone-modifying enzymes. Today, HDAC inhibitors as well as DMA demethylation substances like AZA cytidine are being successfully used in cancer clinics (De Carvalho et al, 2012). The study on epigenetic and cancer has lead to “epigenetic treatment” which is a big step in cancer management.

References

Mattick, J.S. & Makunin I.V. (2006). Non-coding RNA. Human Molec. Genet. 15: R17- R29.

Rodenhiser, D. & Mann, M.  (2006). Epigenetics and human disease: translating basic biology into clinical applications.  C.M.A.J. 174:341-348.

Esteller, M. (2005). Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol 45: 629–56.

De Carvalho, D.D., Sharma, S., You, J.S., Su, S.F., Taberlay, P.C., Kelly, T.K., Yang, X., Liang, G. & Jones, P.A. (2012). DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell 21 (5): 655–67.

Lund, A.H & van Lohuizen, M. (2004). Epigenetics and cancer.  Genes Dev. 18:2315-2335

Fraga, M.F. (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.  Nat. Genet. 37: 391-340

Esteller, M. & Herman, J.G. (2004). Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer. Oncogene 23(1): 1–8.