Ovarian cancer: epigenetics, drug resistance, and progression

Abstract

Ovarian cancer (OC) is one of the most common malignant tumors in women. OC is associated with the activation of oncogenes, the inactivation of tumor suppressor genes, and the activation of abnormal cell signaling pathways. Moreover, epigenetic processes have been found to play an important role in OC tumorigenesis. Epigenetic processes do not change DNA sequences but regulate gene expression through DNA methylation, histone modification, and non-coding RNA. This review comprehensively considers the importance of epigenetics in OC, with a focus on microRNA and long non-coding RNA. These types of RNA are promising molecular markers and therapeutic targets that may support precision medicine in OC. DNA methylation inhibitors and histone deacetylase inhibitors may be useful for such targeting, with a possible novel approach combining these two therapies. Currently, the clinical application of such epigenetic approaches is limited by multiple obstacles, including the heterogeneity of OC, insufficient sample sizes in reported studies, and non-optimized methods for detecting potential tumor markers. Nonetheless, the application of epigenetic approaches to OC patient diagnosis, treatment, and prognosis is a promising area for future clinical investigation.

Keywords: DNA methylation; Epigenetics; Histone modifications; LncRNA; MiRNA; Ovarian cancer.

Fig. 1

Epigenetic processes include DNA methylation, histone modification, non-coding RNA, RNA modification, chromatin remodeling, and genomic imprinting. a DNA methylation is divided into two categories: the hypermethylation of CpG islands and global hypomethylation. b Histone post-translational modifications, including methylation, acetylation, phosphorylation, deamination, ubiquitination, ADP‐ribosylation and proline isomerization. c Non-coding RNA including miRNA, lncRNA, rRNA, tRNA, snRNA, snoRNA, sncRNA, siRNA, etc., act in the nucleus or cytoplasm. d Post-transcriptional modification of RNA through RNA editing and RNA methylation. e Chromatin-remodeling complexes are grouped into four major families: SWI/SNF, INO80, ISWI, and CHD. f Genomic imprinting is an epigenetic process that mainly includes maternal imprinting and paternal imprinting

Fig. 2

Classic molecular mechanisms of DNA methylation, histone modification, and  miRNA. a Genes are silenced by hypermethylation, which is catalyzed by DNA methyltransferases (DNMTs). Genes are expressed when DNA is demethylated, which is catalyzed by DNA methylation inhibitors (DNMTis). b Histone acetyltransferases (HATs) and histone deacetylases (HDACs) maintain a reversible equilibrium state of histone acetylation. c MiRNAs are formed from precursor RNAs that are cleaved by the Drosha and Dicer enzymes. MiRNAs block gene expression by promoting mRNA degradation and by preventing protein translation

Fig. 3

Schematic mechanisms of lncRNA in regulating gene expression. Nuclear lncRNAs modulate gene expression through chromatin modification, transcriptional regulation, RNA splicing and LncRNA–DNA interaction. In the cytoplasm, lncRNAs play a role in miRNA sponge formation, mRNA stability regulation and protein stability control