Abstract
Simple SummaryEpigenetics is a process that allows genetic control, without the involvement of sequence changes to DNA or genes. In cancer, epigenetics is a key event in tumour development that can alter the expression of cancer driver genes and result in genomic instability. Due to the critical role of epigenetics in malignant transformation, therapies that target these processes have been developed to treat cancer. Here, we provide a summary of the epigenetic changes that have been described in a variety of gynaecological cancers. We then highlight how these changes are being targeted in preclinical models and clinical trials for gynaecological cancers.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.
Highlights
Cancer is a multifaceted group of diseases that develop due to an interplay between genetic and epigenetic factors
EP400 acts as a transcriptional corepressor, and KDM5C possesses demethylase activity against the active promoter marks, H34me2 and H3K4me3. This has led to the speculation that the transcriptional repressor activity of EP400 and KDM5C may aid in E2 mediated repression of the E6 and E7 oncoproteins [20]
One study exploring the role of androgen receptor (AC) in endometrial cancer suggested that KDM4B together with AR can activate the well-recognised oncogene, MYC, by removing H3K9me3 marks in endometrial cancer cells with high basal levels of AR [28]
Summary
Cancer is a multifaceted group of diseases that develop due to an interplay between genetic and epigenetic factors. Somatic mutations alone do not account for the tumourigenic characteristics of cancer cells; and epigenetic deregulation of oncogenes and tumour suppressors is another important mechanism contributing to carcinogenesis [1,2]. Epigenetic inhibitors or “epidrugs” are being studied for their potential anti-tumour activity, and may be beneficial for cancers with global dysregulation of gene expression. The potential of these inhibitors to target reversible modifications to the genome, coupled with their ability to influence the expression of multiple genes concomitantly, make them attractive as novel anticancer compounds, through re-expression of tumour suppressor genes. This review will outline and discuss studies pertaining to epigenetic factors with a focus on histone modifying enzymes in common gynaecological cancers, ovarian, endometrial and cervical cancers. The mechanisms by which epigenetics contribute to tumorigenesis and the evidence that implicates epigenetic enzymes, in particular histone modifying enzymes, as treatment targets will be discussed
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