EpiCancer

Epigenetics: The epicentre of cancer or just a minor player?

It is commonly thought that cancer is inherited. This view, however, is not completely accurate. It
is the risk elements that leads to cancer that is inherited - germline mutations of tumour
suppressor genes or mutations in DNA repair mechanism genes. An inheritable element that has
been widely overlooked in the past is epigenetic changes and what role it has in cancer.
Epigenetic inheritance are
changes in gene function
that are not due to
changes to the DNA
sequence but due to stable
changes in the structure of
the DNA and chromatin
that can be inherited
during cell division(1).
These structural changes
can either be the
hypomethylation and
hypermethylation of DNA,
the modification of
chromatin structure and
genetic imprinting loss.
The presence of increased
methyl groups on DNA
can inhibit the expression of genes - it thus functions as a silencer. Hypermethylation of the
promoter regions in genes that encode for tumour suppressing transcripts are thought to an
important cause in the origin of many cancers. Hypermethylation of promoter CpG islands in the
retinoblastoma tumor-suppressor gene was found to be a mechanism in the inactivation of
tumour suppressor genes VHL, hMLH1, and BRCA1.
Hypomethylation (most frequently CpG islands and CT regions) can cause the activation of
genes and is found in both benign and malignant tumours. HRAS and CT oncogenes are
commonly activated by hypomethylation and can lead to the expression of MAGE and the
activation of the antigen CAGE. Hypomethylation are mostly associated with cancers of the
digestive system and the female reproductive system (1-4).
The role of histone modification in cancer was the last epigenetic mechanism discovered. Normal
gene regulation is highly dependant on the methylation of lysine residues in histones. The
methylation of lysine 9 on histone H3 has been found to play a role in the silencing the tumour
suppressor gene, CDKN2A which is associated with melanoma-pancreatic cancer syndrome(1).

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Recent evidence has shown that this methylation of histone H3 can be reversed by the
replacement of histone H3 with the histone variant, H3.3.
Histone acetylation (and the deacetylation of histones) influences the conformation of the
histones by either opening or closing the chromatin structure. These structural changes can
either facilitate or prevent transcription. Enzymes involved in the acetylation of lysine residues
can also change the structure of histones. These enzymes have been found to be implicated in
transformation of normal cells to malignant cells and that numerous viral oncoproteins are
associated with them. The mechanism of this action is not entirely known yet and it is thought
that these enzymes not only influence histone proteins but also nonhistone proteins.
The enzymes that deacetylates histones (HDACs) can be recruited by oncoproteins to silence
genes that can lead to leukemogenesis(5). To date, no evidence has been found to suggest that
mutations in the genes that encode for HDACs play any role in cancer.
Genomic imprinting is the conditioning of genomes during gametogenesis so that certain alleles
from one parent are more expressed in the offspring. Loss of genetic imprinting (LOI) refers to
the disruption of the parental-origin epigenetic modifications. This can include methylation and
chromatin markers. These changes can lead to the silencing or activation of genes. LOI is most
studied in Wilms tumour (embryonal kidney cancer) and was found to be present in 50% - 70%
of tumours(1).
Epigenetic changes of the genome can be used as a biological marker to test individuals to
determine the possibility of cancer developing (by checking the methylation of suppressor genes,
for instance) and starting possible early treatments(2). These changes are also mostly reversible
which can by means of inhibitory drugs or DNA demethylating drugs reverse the effects of the
epigenetic changes. The drugs Vidaza and decitabine (both are DNA demethylating drugs) has
been approved to be used as treatment in myelodysplastic syndrome and leukemia(3+4).
As more and more research is being done on the role of epigenetics in cancer its growing
importance is being fully understood. It can be used as a way of early detection and/or early
treatment by reversing the changes that have been caused by either the hypomethylation and
hypermethylation of DNA, the modification of chromatin structure or the loss of genetic
imprinting. Although this is a promising avenue a lot has to be considered - these treatments may
a well silence or activate other genes. The choice of mechanism for the drug must also be wisely
chosen.

References:
1. Feinberg A, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4(2):143-153.
2. Brower V. Epigenetics: Unravelling the cancer code. Nature. 2011;471(7339):S12-S13.
3. Esteller M. Epigenetics in Cancer. New England Journal of Medicine. 2008;358(11):1148-1159.
4. Laird P. Cancer epigenetics. Human Molecular Genetics. 2005;14(suppl_1):R65-R76.

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5. Dawson M, Kouzarides T. Cancer Epigenetics: From Mechanism to Therapy. Cell.

2012;150(1):12-27.

AnthonyEEngelbrecht13020545