Histone Modifying Enzymes in Gynaecological Cancers

Abstract

Genetic and epigenetic factors contribute to the development of cancer. Epigenetic dysregulation is common in gynaecological cancers and includes altered methylation at CpG islands in gene promoter regions, global demethylation that leads to genome instability and histone modifications. Histones are a major determinant of chromosomal conformation and stability, and unlike DNA methylation, which is generally associated with gene silencing, are amenable to post-translational modifications that induce facultative chromatin regions, or condensed transcriptionally silent regions that decondense resulting in global alteration of gene expression. In comparison, other components, crucial to the manipulation of chromatin dynamics, such as histone modifying enzymes, are not as well-studied. Inhibitors targeting DNA modifying enzymes, particularly histone modifying enzymes represent a potential cancer treatment. Due to the ability of epigenetic therapies to target multiple pathways simultaneously, tumours with complex mutational landscapes affected by multiple driver mutations may be most amenable to this type of inhibitor. Interrogation of the actionable landscape of different gynaecological cancer types has revealed that some patients have biomarkers which indicate potential sensitivity to epigenetic inhibitors. In this review we describe the role of epigenetics in gynaecological cancers and highlight how it may exploited for treatment.

Keywords: epigenetic enzymes; epigenetic modifiers; epigenetic treatment; epigenetics; gynaecological cancers; histone modifiers.

Figure 1

Histone modifying enzymes and epigenetic drugs in gynaecological cancers to restore the balance of epigenetic factors. Left panel; HDACs, KDMs and KMTs are often over-expressed across many gynaecological cancers. Mechanisms include addition of methyl groups and/or removal of acetyl groups at key histone tail residues, resulting in the repression of key tumour suppressor genes. Right panel; Epigenetic intervention via small molecule inhibitors to epigenetic enzymes, or “epidrugs” induces changes in chromatin configuration, resulting in re-expression of tumour suppressor genes. Examples of HDAC inhibitor names are provided, question marks denote that KDM/KMT inhibitors are to be determined. Green wedges represent lysine demethylases (KDMs), yellow wedges represent KMTs, blue wedges represent HDACs, red diamonds represent methyl groups, green diamonds represent acetyl groups, alternating grey and orange circles represent amino acid residues that comprise histone tails, large purple ovals represent histone subunits, triangles with black, dark grey and light grey borders represent HDAC inhibitors, KDM inhibitors and KMT inhibitors respectively.