**16. Definition of epigenetic therapy**

The term epigenetic therapy is now widely used, and involves use of drugs or other epigenome-influencing mechanisms for treatment of human disorders. Recent advances have delineated regulatory mechanisms of the cancer and normal epigenomes and the functional understanding of histone modifications, methylation patterns, and dynamics of nucleosomes [108, 109]. Recent studies in the field of cancer epigenetics have not only defined key targets for cancer management but also provided key insights in drug repurposing for modulating cancer epigenomes [110]. In epigenetic therapy, drugs target three specific protein categories (a) Writers, enzymes that establish epigenetic marks; (b) Readers, proteins that recognize histone and may bring in other protein complexes to change gene expression; and (c) Erasers, enzymes that remove epigenetic marks [111]. Drugs that impede writers of DNA methylation, DNA methyltransferases (DNMT), and erasers (histone deacetylases or HDAC) that regulate histone lysine acetylation are central to epigenetic therapy in cancer treatment. HDACs and DNMTs are mostly linked with transcriptional repression. Thus, inhibiting HDACs and DNMTs can upregulate expression of involved genes with many consequences for downstream pathways of this gene activation.

Cytidine analogues inhibit DNMTs by blocking their catalytic and likewise induces their degradation [112]. Also, the degradation of DNMTs can remove key scaffolding properties that may function for repression of transcription [113, 114]. Tumors show significant alterations in DNA methylation of cytosines at CpG dinucleotides such as loss of methylation at regions such as repetitive elements that must be silenced for genome stability and gain of methylation at the promoter regions of tumor suppressor and other genes [115]. Inhibitors targeting DNMTs promote reactivation of tumor suppressor, silenced by promoter DNA methylation [116]. DNA methylase inhibitors (DNMTi) showed augmented apoptosis, decreased cell cycle activity, and reduced stemness in a transient exposure to several cancer cells (**Figure 6**) [117]. DNMTis such as 5-azacytidine and 5-aza-20-deoxycytidine showed robust efficacy in treatment of hematological disorders and has been approved by FDA for the treatment of myelodysplastic syndrome (MDS) [118]. Several clinical studies are undergoing presently to study the effect of epigenetic therapy in cancer treatment **Table 7**.

Histone modifications by acetylation plays a central role in epigenetic gene regulation by altering the condensation status of chromatin, modulating the accessibility of transcription factors to target DNA sites. Histone acetyltransferases (HAT) and HDACs maintain the acetylation state of histones of nucleosomes. Inhibitors targeting HDACs known as (HDACi) are presently approved for the treatment of peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), although it is yet to be known as why these two cancers are highly sensitive towards HDACi [119, 120]. Also, it has been observed that HDACi show dependency of, compound, dose and pleotropic characteristics. Many of the HDACi directly affect acetylation of histone proteins and modulate epigenetic changes while some affect acetylation of non-histone or cytoplasmic proteins [121]. Besides, it has been observed that transient exposure of tumor cells to low doses of DNMTs, followed by HDACi treatment increases gene expression of hypermethylated genes.

*Integrating Immunotherapy with Chemotherapy: A New Approach to Drug Repurposing DOI: http://dx.doi.org/10.5772/intechopen.100183*

#### **Figure 6.**

*Flowchart representing the overall effects of epigenetic therapy.*


#### **Table 7.**

*Clinical trials for epigenetic inhibitors.*
