Epigenetic Mechanisms and Therapeutic Targets in Chemoresistant High-Grade Serous Ovarian Cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is the most common ovarian cancer subtype, and the overall survival rate has not improved in the last three decades. Currently, most patients develop recurrent disease within 3 years and succumb to the disease within 5 years. This is an important area of research, as the major obstacle to the treatment of HGSOC is the development of resistance to platinum chemotherapy. The cause of chemoresistance is still largely unknown and may be due to epigenetics modifications that are driving HGSOC metastasis and treatment resistance. The identification of epigenetic changes in chemoresistant HGSOC enables the development of epigenetic modulating drugs that may be used to improve outcomes. Several epigenetic modulating drugs have displayed promise as drug targets for HGSOC, such as demethylating agents azacitidine and decitabine. Others, such as histone deacetylase inhibitors and miRNA-targeting therapies, demonstrated promising preclinical results but resulted in off-target side effects in clinical trials. This article reviews the epigenetic modifications identified in chemoresistant HGSOC and clinical trials utilizing epigenetic therapies in HGSOC.

Keywords: DNA methylation; DNA methyltransferase inhibitors; chemoresistance; epigenetic modifications; high-grade serous ovarian cancer; histone acetylation; histone deacetylase inhibitors; microRNA.

Figure 1

This diagram summarises the complexity of epigenetic modifications. DNA methylation, histone modification (histone acetylation in this diagram), and miRNA expression influence the epigenetics of ovarian cancer development and progression towards treatment resistance. Hypermethylation of gene promoters is associated with suppression of gene expression, a process catalysed by DNA methyl transferase (DNMT) enzymes. HAT enzymes add acetyl groups to the histone surface, which increases the accessibility of RNA polymerase II, leading to gene expression. HDAC enzymes remove the acetyl groups from histones and restrict access by RNA polymerase, resulting in decreased gene expression. miRNAs target mRNAs by binding with their 3′-UTR, leading to mRNA degradation or translational repression. Figure adapted from “Cancer Epigenetics” and “miRNA in Cancer”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates (accessed on 4 Novermber 2021).