One therapeutic approach for targeting chemoresistance may be to reverse the epigenetic marks in chemoresistant cells. Small interfering RNA (siRNA) raised against DNMT1 has been shown to restore estrogen receptor-alpha (ERα) signaling in ERα-negative human breast cancer cell lines, thus enabling the use of antiestrogens as therapy [
124] while overexpression of a dominant-negative histone H3 lysine 27 mutant (H3K27R) de-repressed epigenetically silenced tumor suppressor genes and reversed drug-resistance in ovarian cancer cells [
65]. Such studies provide a proof-of-concept that epigenetic alteration can directly impact ovarian cancer chemosensitivity. Several chemical inhibitors of epigenetic enzymes, targeting DNMT and histone deacetylases (HDAC), have shown promising anti-tumorigenic effects for some malignancies (reviewed in [
125,
126]. Treatment of cancer cells with the DNMT inhibitors 5-aza-dC, decitabine and zebularine show promise in reversal of repressive histone mark patterns and resensitization of ovarian cancer cells to chemotherapy [
127,
128], and several are currently in clinical trials [
125,
126].
Inhibitors of class I histone deacetylases (HDACi) have been shown to suppress ovarian cancer cell growth and provide an option for clinical use [
129]. HDACi are divided into four groups: short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides, and benzamides. The small-chain fatty acids butyrate, and valproic acid (VPA) (originally regarded as anti-epileptic drug), were the first known HDAC inhibitors [
130,
131]. Although not exceedingly specific, these compounds laid the foundation of HDACi and are tools for studying the structure and mechanism of HDACi. Newer HDACi, like suberoylanilide hydroxamic acid (SAHA), have been rationally designed with high affinity for the zinc ion within the HDAC catalytic domain [
132]. The HDACi depsipeptide has the capability to activate silenced genes by decreasing both CpG and H3K9 methylation at gene promoters, suggesting HDAC inhibition induces additional chromatin regulation aside from histone acetylation [
133]. Indeed, it has been established that combinations of DNA methylation and HDACi are more potent for gene re-expression than either alone [
97,
134]. VPA, SAHA, depsipeptide, and other HDACi are currently in clinical trials, alone and in combinations with DNMTi (reviewed in [
125,
126]). Combinatorial epigenetic therapy may also be useful in targeting stem cells; DNMT1 gene knockout combined with HDACi has been shown to be lethal to embryonic stem cells [
135]. Such therapy may therefore extended to targeting against cancer stem cells. One potential drawback of epigenetic therapy is the possibility that these agents can inhibit or reverse normal developmental processes or accelerate cellular differentiation and tissue ageing [
136‐
138]. This may not be surprising since most HDACi and DNMTi compounds were originally discovered as differentiating agents [
126,
139‐
141], and must be considered alongside efficacy.