MOLECULAR GENETICS

JONATHAN MILHOMENS
Cancer epigenetics

Epigenetics defines all heritable modifications in gene expression that are not part
of the actual DNA sequence. The information contained in epigenetics is showed in the
cell in several forms that might include DNA methylation, modification of histones proteins
such as methylation, acetylation, etc., and even microRNA expression. These patterns
has been studied a lot in the past decade, in the aspects of cell malignancy, and has
seem to be an important feature in the concept that cancer is a disease of abnormalities
in genetics, as well as, in epigenetics (EGGER G. et al, 2004; CAMPBELL & TUMMINO,
2014; BAYLIN & JONES, 2011).
Cancer is commonly caused by a whole different types of genetic defects
(mutations, amplifications, deletions, translocations, etc.) that affects the cell division
machinery and provides the cancer the advantage to multiply indefinitely and in some
point, metastasize. Cancer has another important secondary molecular origin, where the
role of the chromatin modifications and architecture has a great influence to gene expression, so called the cancer epigenome, which brings abnormalities based on heritable
alterations in somatic cells, not involved in primary DNA sequence changes
(HATZIMICHAEL & CROOK, 2013).
The first epigenetic correlation between cancer and epigenetics was identified by
Andy Feinberg and Bert Vogelstein. They showed a loss of DNA methylation at CpG
dinucleotides, in 1982, wondering that the mechanism caused the high-frequency
mutations and plasticity in some cancers. They used Southern blotting to screen DNA
molecules digested with a restriction enzyme (methylation-sensitive restriction enzymes)
and they saw that a significant proportion of CpGs, methylated in normal tissues, were
not methylated in cancer cells. The patterns of DNA methylation and chromatin
architecture are deeply changed in neoplasia and harbor genome-wide losses of DNA
methylation, and also regional gains. Nowadays, it is well recognized that tumorigenesis
is a really important process involving several genetic and epigenetic alterations, in which
the latter always termed epimutations, contributes massively transforming of normal cells
into a malignant phenotype (FEINBERG & TYCKO, 2004).

One of the most well studied epigenetic changes in humans is DNA methylation,
however, it becomes extremely noticed that DNA methylation does not act by itself, but
rather intrinsically linked to other changes, such as histone modifications. When linked to
cancer, DNA methylation, ranging from 0.5 to 5 kb that are CG rich and called CpG
islands, are usually found in the promoters of the genes. Usually, half of all gene
promoters have CpG islands, and when methylated they lead to transcriptional errors.
The histones are not only responsible for Nucleic Acid packaging elements, but also
critically regulates gene expression. The histone tails may undergo a lot of posttranslational modifications, (acetylation, methylation, phosphorylation, ubiquitylation)
those modifications constitute a code, named the histone code. These modifications
alter the chromatin structure and among various other biological processes, it is related
to transcriptional repression, gene activation, and DNA repair. One example in cancer is
the process of genomic hypo-methylation that occurs mostly in DNA-repetitive regions,
resulting in activation and expression of genes that helps cell growth and tumour
metastasis. In other hand, some site-specific increases in CpG methylation in areas of
the epigenome with high density of CpG, (CpG islands) causing transcriptional silencing
of tumour suppressor genes (EGGER G. et al, 2004; CAMPBELL & TUMMINO, 2014;
BAYLIN & JONES, 2011; HATZIMICHAEL & CROOK, 2013).
Although cancer epigenetics is well understood and noted, there are still some
issues that keep going into the limit of the complete acceptance and still stimulate
debates. The relationship between the mechanisms of epigenetic inheritance, other than
DNA methylation, is still a large and complicated issue, and cancer epigenetics can
probably advance profoundly when these processes is better understood.

References:
BAYLIN & JONES. A decade of exploring the cancer epigenome biological and translational
implications. Nature Reviews. Cancer. Vol. 11, pag. 726-734, 2011.
CAMPBELL & TUMMINO. Cancer epigenetics drug discovery and development: The
challenge of hitting the mark. Journal of Clinical Investigation. Vol. 124, N. 1, pag. 64-69, 2014.
EGGER, G. et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature.
Vol. 429, pag. 457-463, 2004.
FEIBERG & TYCKO. The history of cancer epigenetics. Nature Reviews. Cancer. Vol. 4, pag.
143-153, 2004.
HATZIMICHAEL & CROOK. Cancer epigenetics: New therapies and new challenges. Journal
of Drug Delivery. Vol. 2013, 9 pages, 2013.