Abstract
Like other cancers, most gynecologic cancers are caused by aberrant expression of cancer-related genes. Epigenetics is one of the most important gene expression mechanisms, which contribute to cancer development and progression by regulating cancer-related genes. Since the discovery of differential gene expression patterns in cancer cells when compared with normal cells, extensive efforts have been made to explore the origins of abnormal gene expression in cancer. Epigenetics, the study of inheritable changes in gene expression that do not alter DNA sequence is a key area of this research. DNA methylation and histone modification are well-known epigenetic mechanisms, while microRNAs and alternative splicing have recently been identified as important regulators of epigenetic mechanisms. These mechanisms not only affect specific target gene expression but also regulate the functioning of other epigenetic mechanisms. Moreover, these diverse epigenetic regulations occur simultaneously. Epigenetic regulation of gene expression is extraordinarily complicated and all epigenetic mechanisms to be studied at once to determine the exact gene regulation mechanisms. Traditionally, the contribution of epigenetics to cancer is thought to be mediated through the inactivation of tumor suppressor genes expression. But recently, it is arising that some oncogenes or cancer-promoting genes (CPGs) are overexpressed in diverse type of cancers through epigenetic derepression mechanism, such as DNA and histone demethylation. Epigenetic derepression arises from diverse epigenetic changes, and all of these mechanisms actively interact with each other to increase oncogenes or CPGs expression in cancer cell. Oncogenes or CPGs overexpressed through epigenetic derepression can initiate cancer development, and accumulation of these abnormal epigenetic changes makes cancer more aggressive and treatment resistance. This review discusses epigenetic mechanisms involved in the overexpression of oncogenes or CPGs via epigenetic derepression in gynecologic cancers. Therefore, improved understanding of these epigenetic mechanisms will provide new targets for gynecologic cancer treatment.
Highlights
Cancer is a heterogeneous disease caused by uncontrollable cell division [1]
Both tumor suppressor genes (TSGs) and oncogenes or cancer-promoting genes (CPGs) are abnormally expressed in diverse cancers via various mechanisms, and each gene has a specific function according to the characteristics of specific cancers
Growing evidences have shown that epigenetic derepression mechanisms including DNA demethylation, gain of active histone modifications, TSmiRNA downregulation, oncogenic alternative splicing and hypomethylation of repeated sequences play critical roles in cancer development
Summary
Cancer is a heterogeneous disease caused by uncontrollable cell division [1]. Early research recognized cancer as a genetic disorder of proliferation-related genes, but recent studies have approached cancer multidirectionally, examining resistance to cell death, angiogenesis, invasion, metastasis, and other properties [2]. MiR7/miR-218 can modify DNA methylation and histone modification status by decreasing homeobox B3 (HOXB3) expression [76], and miR-28/miR-505 can affect alternative splicing through SRSF1 inhibition [77] With these recent findings, integrated analysis of epigenetic studies has gradually progressed through the efforts of diverse groups. Kwon et al [13] have shown the importance of simultaneous epigenetic changes in CLDN3 and CLDN4 overexpression They have found that CLDN3 and CLDN4 repression in normal ovarian cells is associated with “bivalent” histone modification, and simultaneous increase in H3K4me and decrease in H4K20me and H3K27me work together to induce CLDN3 and CLDN4 expression levels [13]. Epigenetic study of 66 primary ovarian tumors and 3 ovarian cancer cell lines has revealed that DNA methylation and chromatin www.frontiersin.org
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