Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 329-345 http://medscipublisher.com/index.php/cge 339 resistance and improve clinical outcomes for patients with ovarian cancer. 8 Therapeutic Potential of Targeting Epigenetic Regulation of ncRNAs in Ovarian Cancer 8.1 Current therapies targeting ncRNAs: use of DNA methyltransferase and histone deacetylase inhibitors Current therapeutic strategies targeting non-coding RNAs (ncRNAs) in ovarian cancer primarily involve the use of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors. These inhibitors work by reversing the epigenetic modifications that silence tumor suppressor genes, thereby reactivating their expression and inhibiting cancer progression. DNMT inhibitors, such as 5-aza-2'-deoxycytidine (ADC), have shown efficacy in reactivating silenced genes by demethylating DNA. HDAC inhibitors, like trichostatin A (TSA), induce histone hyperacetylation, leading to changes in chromatin structure and gene expression. TSA has been shown to decrease the stability of DNMT3B mRNA, reducing de novo DNA methylation activities, which further contributes to the reactivation of silenced genes (Xiong et al., 2005). The combination of DNMT and HDAC inhibitors has been particularly effective. For instance, the concomitant inhibition of these pathways has demonstrated promising results in various cancers, including ovarian cancer. This combination therapy can lead to histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9, which collectively contribute to the reactivation of tumor suppressor genes (Rabal et al., 2021; Ružić et al., 2022). 8.2 Emerging therapeutic approaches: Synthetic ncRNA mimics and CRISPR-based epigenetic editing Emerging therapeutic approaches for targeting ncRNAs in ovarian cancer include the use of synthetic ncRNA mimics and CRISPR-based epigenetic editing. Synthetic ncRNA mimics, such as miRNA mimics, are designed to restore the function of tumor-suppressive miRNAs that are downregulated in cancer. For example, miR-34 and miR-16 mimics have reached phase I clinical trials for the treatment of liver cancer and mesothelioma, demonstrating the potential of this approach (Slabý et al., 2017; Wang, 2024). CRISPR-based epigenetic editing is another innovative strategy that allows for precise modifications of the epigenome. This technology can be used to target specific epigenetic marks, such as DNA methylation or histone modifications, at particular genomic loci. By using CRISPR-dCas9 fusion proteins, researchers can recruit epigenetic modifiers to specific DNA sequences, enabling targeted demethylation or acetylation. This approach holds great promise for reactivating silenced tumor suppressor genes and inhibiting oncogenes in ovarian cancer (Gelato et al., 2016; Huang et al., 2019). 8.3 Challenges and opportunities: limitations of current approaches and potential improvements Despite the promising potential of targeting epigenetic regulation of ncRNAs in ovarian cancer, several challenges remain. One major limitation is the specificity of current epigenetic therapies. DNMT and HDAC inhibitors can affect a broad range of genes, leading to off-target effects and potential toxicity. Improving the specificity of these inhibitors is crucial for minimizing side effects and enhancing therapeutic efficacy (Cheng et al., 2019; Ružić et al., 2022). Another challenge is the delivery of synthetic ncRNA mimics and CRISPR-based epigenetic editors to tumor cells. Efficient and targeted delivery systems are needed to ensure that these therapeutic agents reach their intended targets without being degraded or causing adverse effects in non-target tissues. Advances in nanoparticle-based delivery systems and viral vectors hold promise for overcoming these delivery challenges (Slabý et al., 2017). Furthermore, the development of resistance to epigenetic therapies is a significant concern. Cancer cells can adapt to epigenetic modifications, leading to the re-silencing of tumor suppressor genes or the activation of alternative oncogenic pathways. Combination therapies that target multiple epigenetic regulators or combine epigenetic therapies with other treatment modalities, such as chemotherapy or immunotherapy, may help to overcome resistance and improve treatment outcomes (Thompson et al., 2023).
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