Abstract
The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, most studies have focused on the epigenetic inactivation of tumor suppressor genes during tumorigenesis and little is known about the epigenetic activation of cancer-associated genes, except for the DNA hypomethylation of some genes. Recently, we reported that the overexpression of cancer-promoting genes in ovarian cancer is associated with the loss of repressive histone modifications. This discovery suggested that epigenetic derepression may contribute to ovarian tumorigenesis by constituting a possible mechanism for the overexpression of oncogenes or cancer-promoting genes in tumors. The emerging importance of epigenetic aberrations in tumor initiation and in the regulation of cancer-initiating cells, suggests that epigenetically regulated genes may be promising therapeutic targets and biomarkers. Given that the current challenges in ovarian cancer include the identification of biomarkers for early cancer detection and the discovery of novel therapeutic targets for patients with recurrent malignancies undergoing chemotherapy, understanding the epigenetic changes that occur in ovarian cancer is crucial. This review looks at epigenetic mechanisms involved in the regulation of cancer-associated genes, including the contribution of epigenetic derepression to the activation of cancer-associated genes in ovarian cancer. In addition, possible epigenetic therapies targeting epigenetically dysregulated genes are discussed. A better understanding of the epigenetic changes in ovarian cancer will contribute to the improvement of patient outcomes.
Highlights
Ovarian cancer is the most lethal gynecological malignancy [1]
It is generally held that the activation of oncogenes occurs through genetic changes, including amplification and mutation, whereas tumor suppressor genes are inactivated by events such as promoter methylation, gene deletion and loss of heterozygosity (LOH)
Growing evidence supports the importance of epigenetic changes in tumorigenesis as much as the classical, and better known, genetic changes
Summary
Ovarian cancer is the most lethal gynecological malignancy [1]. Due to difficulties in early detection, most ovarian cancers are diagnosed at an advanced stage. As is well known in other forms of human tumorigenesis, epithelial ovarian cancers are caused by both multiple genetic and epigenetic alterations [4] They develop due to the accumulation of genetic changes in multiple oncogenes and tumor suppressors. Several signaling pathways are frequently activated in ovarian cancer, including the Ras-MAPK signaling pathway, the PI3K pathway, IL6-IL6R-Jak2-STAT3 signaling, and the LPA and NF-kB signaling pathways, amongst others [2,4] Based on these genetic aberrations, several potential anti-cancer targets have been identified recently and novel targeted therapeutics are under development [2,5]. CICs, or drug resistant ovarian cancers, are discussed as promising approaches for the efficient treatment of ovarian cancer
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