Therapeutic modulation of epigenetic drivers of drug resistance in ovarian cancer

Abstract

Epigenetic changes in tumours are associated not only with cancer development and progression, but also with resistance to chemotherapy. Aberrant DNA methylation at CpG islands and associated epigenetic silencing are observed during the acquisition of drug resistance. However, it remains unclear whether all of the observed changes are drivers of drug resistance, causally associated with response of tumours to chemotherapy, or are passenger events representing chance DNA methylation changes. Systematic approaches that link DNA methylation and expression with chemosensitivity will be required to identify key drivers. Such drivers will be important prognostic or predicitive biomarkers, both to existing chemotherapies, but also to epigenetic therapies used to modulate drug resistance.

Keywords: CpG islands; DNA methylation; drug resistance; epigenetics; histones; ovarian cancer; therapies.

Figure 1.

Possible targets for epigenetic therapy approaches in chemoresistant cells. Aberrant DNA hypermethylation (dark circles) at CpG islands can lead to transcriptional inactivation of genes and is frequently observed in tumours. Inhibition of the enzymes catalysing DNA methylation (DNMTs) leads to a genome-wide decrease of DNA methylation levels, thereby potentially re-activating vital anticancer genes. Each histone modification is established via specific enzymes (HDACs and HKMTs) catalysing the addition or removal of certain marks. Targeting aberrant hypoacetylation via HDACi can result in the re-expression of former transcriptionally incompetent chromatin. Similarly, the inhibition of certain aberrantly active histone methyltransferases (HKMTs) prevents methyl marks which may lead to repression of genes, as seen following the binding of HP1 (orange circles) to H3K9me3. Next to the two major epigenetic mechanisms of DNA methylation and histone modification, aberrant expression of miRNAs (small non-protein-coding RNAs of 21–23 nucleotides) has been correlated with tumourigenesis. Here, miRNAs potentially act on two pathways, the transcriptional silencing mechanism and the translational silencing mechanism. If in either case the miRNAs promiscuously bind sequences, for instance via mutation, the former specific gene regulation is out of control, possibly contributing to tumourigenesis and chemoresistance. In ovarian cancer, for example, downregulation of the miRNA let-7i increases resistance to cisplatin and is associated with shorter progression-free survival time of patients with late-stage ovarian cancer [Yang et al. 2008]. Although not yet available, gene therapy may be a tool to either re-establish lost endogenous miRNA expression or silence aberrant miRNA expression thereby complementing existing epigenetic therapies.