**2. Epigenetic aberrations in ovarian cancer**

### **2.1 DNA methylation**

One of the most common methods of epigenetic modulation is through DNA methylation. Modification of cytosine residues in CpG dinucleotides or CpG islands by methylation leads to transcriptional silencing in vertebrates, however, non-CpG methylation has also been identified in stem cells [49]. Typically, small amounts of CpG island promoters are methylated in normal cells, however, in the presence of hypermethylation, tumorigenesis is often incited [50]. The particular enzymes that are responsible for DNA methylation are DNA methyltransferases (DNMTs) which include DNMT1, DNMT3A, DNMT3A, DNMT3B, and DNMT3C. These enzymes are classified as either *de novo* or maintenance groups, of which *de novo* are more specific to stem cell expression (DNMT3s) whereas DNTM1 is involved in maintenance of DNA methylation during cell division [51].

Both DNA hypomethylation and gene promoter DNA hypermethylation are major oncogenic driving factors. Specifically, hypermethylation of promoters on tumor suppressor genes BRCA 1 and BRCA 2 lead to their silencing and subsequent inactivation of DNA repair driving the development of malignancies such as breast and ovarian cancers [51, 52]. However, the earliest methylation errors were of reduced activity resulting in increased mutation rates. Notably, transcription of repeats, transposable elements (TEs) and oncogenes occurred secondary to changes from hypomethylation through the loss of DNMT1 function [41, 53].

### **2.2 Histone acetylation**

DNA is packaged as chromatin which is composed of nucleosomes. In turn, the nucleosome is comprised of histone proteins (H3, H4, H2A, H2B) which can similarly undergo many modifications and affect DNA transcription, replication and repair [54]. A "histone code" exists in order to regulate chromatin structure through several different histone modifications, which can lead to either activation or repression dependent on the residues and type of modification such as acetylation, ubiquitylation, sumoylation and phosphorylation [40, 55] (**Figure 1**). Dysregulation of any of these functions can lead to oncogenic activation or even the silencing of tumor suppressor genes.

In comparison to DNA methylation, errors in chromatin modification in the development of epithelial ovarian cancers is less understood but also pertinent. The overexpression of class I histone deacetylases (HDACs) has been identified in several cancers, with a prominent association identified in high risk ovarian of serous and clear cell subtypes. In addition, an unfavorable prognostic correlation was seen in patients with endometrioid histologies [56].

### **2.3 MicroRNA dysregulation**

Along with histone modification and methylation dysregulation, cancer cells are prone to errors in microRNA (miRNA) regulation. MiRNAs are small non-coding

**239**

**Figure 1.**

*Novel Indications of Epigenetic Therapy in Ovarian Cancer*

RNAs of 19–22 nucleotides in length which regulate the expression of certain genes either through degradation or inhibition of target mRNA [57]. The expression of epigenetic regulators (DNMTs and HDACs) are controlled by these miRNAs in a feedback loop of which when dysregulated, can lead to carcinogenic potential [58]. Genome analysis reveals condensed areas of miRNAs in cancer-associated genomic regions signifying that dysregulation of these particular areas could lead to aberrant expression [59]. With regard to epithelial ovarian cancer development, the aberrant expression of miRNAs can emulate oncogenic or tumor suppressor activity [60]. The overexpression of some types of miRNA as well as decreased activity of others were more closely correlated with ovarian cancer cells in comparison to healthy ovarian epithelial cells in several studies [61, 62], indicating another potential for

DNA methylation inhibitors (DNMTis) are deoxycytosine analogs. DNMTis prevent methyl group transfer by covalently binding to and trapping methyltransferases [63]. The simplest way to understand the effect of DNMTis is through their effect on oncogenes and tumor suppressor genes [64]. BRCA1 and BRCA2 are oncogenes that when hypermethylated, can lead to a variety of cancers including ovarian cancer [65]. In a similar way, demethylation of tumor suppressor genes like p53, MLH1, H1C1, p16, E-cadherin and APC, can also play a role in the genetic instability that leads to the development of ovarian cancer, its propagation and chemoresistance [64]. Indeed, both demethylation and hypermethylation of the genome have been associated with the development of platinum resistance in ovarian cancer [64]. Consequently, DNMTis have been shown in preclinical models to

The most commonly utilized DNA methyltransferase inhibitors are 5-azactidine (AZA) and decitabine (5-aza-2'deoxycytidine) [63]. Both were developed in the 1960s for the treatment of hematologic malignancies and are currently FDA approved for myelodysplastic syndromes. Both AZA and decitabine have demonstrated some efficacy in clinical and pre-clinical ovarian cancer studies, however, their dose-limiting myelotoxicity limits their practical use. As they can be toxic,

early diagnostic screening and opportunity for intervention.

restore chemosensitivity and restore normal epigenetics [66].

**3. The clinical application of epigenetic therapies**

*The effect of histone acetylation and deacetylation on DNA transcription.*

**3.1 DNA methylation inhibitors (DNMTis)**

*DOI: http://dx.doi.org/10.5772/intechopen.98187*

*Novel Indications of Epigenetic Therapy in Ovarian Cancer DOI: http://dx.doi.org/10.5772/intechopen.98187*

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**2. Epigenetic aberrations in ovarian cancer**

nance of DNA methylation during cell division [51].

**2.1 DNA methylation**

**2.2 Histone acetylation**

silencing of tumor suppressor genes.

**2.3 MicroRNA dysregulation**

in patients with endometrioid histologies [56].

a 35% objective response rate after administration of decitabine followed by carboplatin among platinum resistant ovarian cancer patients [48]. Therefore, current research is concentrated on the development of treatment methodologies involving the use of classic chemotherapy in combination or sequentially with epigenetic

One of the most common methods of epigenetic modulation is through DNA methylation. Modification of cytosine residues in CpG dinucleotides or CpG islands by methylation leads to transcriptional silencing in vertebrates, however, non-CpG methylation has also been identified in stem cells [49]. Typically, small amounts of CpG island promoters are methylated in normal cells, however, in the presence of hypermethylation, tumorigenesis is often incited [50]. The particular enzymes that are responsible for DNA methylation are DNA methyltransferases (DNMTs) which include DNMT1, DNMT3A, DNMT3A, DNMT3B, and DNMT3C. These enzymes are classified as either *de novo* or maintenance groups, of which *de novo* are more specific to stem cell expression (DNMT3s) whereas DNTM1 is involved in mainte-

Both DNA hypomethylation and gene promoter DNA hypermethylation are major oncogenic driving factors. Specifically, hypermethylation of promoters on tumor suppressor genes BRCA 1 and BRCA 2 lead to their silencing and subsequent inactivation of DNA repair driving the development of malignancies such as breast and ovarian cancers [51, 52]. However, the earliest methylation errors were of reduced activity resulting in increased mutation rates. Notably, transcription of repeats, transposable elements (TEs) and oncogenes occurred secondary to changes

DNA is packaged as chromatin which is composed of nucleosomes. In turn, the nucleosome is comprised of histone proteins (H3, H4, H2A, H2B) which can similarly undergo many modifications and affect DNA transcription, replication and repair [54]. A "histone code" exists in order to regulate chromatin structure through several different histone modifications, which can lead to either activation or repression dependent on the residues and type of modification such as acetylation, ubiquitylation, sumoylation and phosphorylation [40, 55] (**Figure 1**). Dysregulation of any of these functions can lead to oncogenic activation or even the

In comparison to DNA methylation, errors in chromatin modification in the development of epithelial ovarian cancers is less understood but also pertinent. The overexpression of class I histone deacetylases (HDACs) has been identified in several cancers, with a prominent association identified in high risk ovarian of serous and clear cell subtypes. In addition, an unfavorable prognostic correlation was seen

Along with histone modification and methylation dysregulation, cancer cells are prone to errors in microRNA (miRNA) regulation. MiRNAs are small non-coding

from hypomethylation through the loss of DNMT1 function [41, 53].

regimens in order to overcome chemoresistance and improve outcomes.

**238**

**Figure 1.** *The effect of histone acetylation and deacetylation on DNA transcription.*

RNAs of 19–22 nucleotides in length which regulate the expression of certain genes either through degradation or inhibition of target mRNA [57]. The expression of epigenetic regulators (DNMTs and HDACs) are controlled by these miRNAs in a feedback loop of which when dysregulated, can lead to carcinogenic potential [58]. Genome analysis reveals condensed areas of miRNAs in cancer-associated genomic regions signifying that dysregulation of these particular areas could lead to aberrant expression [59]. With regard to epithelial ovarian cancer development, the aberrant expression of miRNAs can emulate oncogenic or tumor suppressor activity [60]. The overexpression of some types of miRNA as well as decreased activity of others were more closely correlated with ovarian cancer cells in comparison to healthy ovarian epithelial cells in several studies [61, 62], indicating another potential for early diagnostic screening and opportunity for intervention.
