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Page 272 Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010

In 1896, Baldwin postulated that individuals within a population with the “correct” allele could choose a new
environment so resulting in a permanently changed evolutionary development within that environment .
[1]
It is now more than 60 years since Waddington , following up this approach, introduced the term
[2,3]
“epigenetics” to describe the concept that a characteristic acquired within a total population as a response
to an environmental stimulus could be inherited in the absence of DNA mutations. For example phenotypic
modifications can occur through the alteration of gene expression without any modification to the DNA
sequence of the gene itself. Although the concept was not readily accepted at the time, epigenetics has
subsequently become an important aspect of genetics and evolutionary theory, and is of particular interest
in the study of cancer initiation, development and possible resolutions.

Specifically, epigenetic modifications involve DNA methylation, nucleosome repositioning, histone post-
translational modifications and post-transcriptional gene regulation by miRNAs . Histone modifications
[4]
can affect chromatin structure resulting in the passage of heritable changes to the next generation. The role
of histone epigenetic modifications in ovarian cancer has been comprehensively considered in a review by
Yang et al. . Although they have compiled an impressive listing of histone modifications, they considered
[5]
that such studies are only at an early stage. Nevertheless, there are a number of epigenetic inhibitors being
considered with protein modifying drugs already under clinical trials for ovarian cancers. Currently, there
appears to be a low specificity for such compounds.

The major form of treatment for ovarian cancers, evolved from earlier studies on the use of platinum
compounds inhibiting Escherichia coli cell division and solid tumors involves the use of platinum containing
molecules . A range of such compounds has been developed namely, cisplatin, carboplatin, oxaliplatin,
[6,7]
nedaplatin and lobaplatin, the most commonly used for ovarian cancer treatment being cisplatin and
carboplatin.

In the present review, we will examine DNA methylation and their involvement in the different forms of
ovarian cancer together with the epigenetics of both histones and miRNAs and their possible roles concerning
the reversal of resistance to cis- and carboplatin in ovarian cancer treatment.

CHARACTERISTICS OF DNA METHYLATION
Similarities between the early stages of normal embryological development and cancer development have
been noted since before the mid 20th century. Epigenetic alterations involving DNA methylation can
be considered as such an example, DNA methylation being a basic step essential to the early stages of
embryogenesis. However, cancer initiation also involves alterations of DNA methylation in the silencing of
tumor suppressor genes, the activation of oncogenes and the initiation of metastases. In particular, aberrant
DNA methylation in cancer can be directly linked to drug resistance .
[8]
DNA methylation normally occurs on the cytosine residues adjacent to a guanine residue (CG dinucleotides),
the methyl group from S-adenosylmethionine being attached to cytosine by DNA methyltransferase.
Thus, DNA modification involves 5-methylcytosine, 5-formylcytosine, 5-hydroxymethylcytosine and
5-carboxylcytosine . The CG residues may be present singly along the DNA strands and tend to be
[9]
constantly methylated. Alternatively, they may be present in clusters of 1000-2000 residues along the DNA
in the form of CpG islands that are associated with gene promoters. Hence, if hypomethylated, the genes
are active and if hypermethylated, the genes are silenced . In many cancers, including ovarian cancer, a
[10]
decrease in the global methylation of the heterochromatic chromosome regions results in the activation of a
number of oncogenes, whilst the locus-specific hypermethylation of specific CpG island regions associated
with promoters of tumor suppressor genes results in their inactivation [4,11-13] . Nevertheless, when methylation
occurs, there are cases when only one allele maybe methylated and the other not. Hence, it depends on which