Cancer Genetics and Epigenetics, 2025, Vol.13, No.2, 77-89 http://medscipublisher.com/index.php/cge 84 6.2 Epigenetic reprogramming leading to drug resistance Epigenetic reprogramming, including histone modification, is an important cause of drug resistance in prostate cancer. Histone methyltransferases, such as those responsible for H3K4 methylation, are crucial in regulating gene expression and are also related to the development of drug-resistant cancers. Nowadays, scientists are developing inhibitors targeting these enzymes to address the drug resistance issues of various cancers, including castration-resistant prostate cancer (Yang et al., 2021). Furthermore, the deletion of some important tumor suppressor genes (such as RB1, TP53, PTEN), as well as the increase of oncogenes (such as MYCN, AURKA), are all related to epigenetic alterations. These changes can cause cancer cells to "transform" and develop resistance to endocrine therapy. These epigenetic changes include DNA methylation and histone methylation, which can affect the differentiation direction of cancer cells and cause disorders unrelated to androgen receptors, such as neuroendocrine prostate cancer (Imamura et al., 2023). The use of epigenetic regulatory drugs, such as histone deacetylase inhibitors, has great potential in reactivating tumor suppressor genes and enhancing the sensitivity of cancer cells to treatment (Perry et al., 2010). 6.3 Clinical significance of histone modification in drug resistance treatment Histone modification has a high clinical value in the treatment of drug resistance. Epigenetic changes, including histone modifications, are expected to become indicators for the diagnosis and prognosis determination of prostate cancer. These modifications can flexibly regulate gene expression and also interact with important biological processes such as androgen receptor signal transduction. Therefore, they are excellent therapeutic targets (Conteduca et al., 2021). Epigenetic changes can be reversed, which enables the implementation of innovative therapeutic strategies, such as restoring cells to a "normal" epigenetic state through treatment. For instance, the use of histone deacetylase inhibitors and demethylating drugs can reactivate dysfunctional tumor suppressor genes, providing new treatment options for patients with advanced prostate cancer (Perry et al., 2010). Furthermore, treatment targeting histone methyltransferases and their related pathways helps overcome drug resistance and improve the efficacy of existing therapies (Yang et al., 2020). Combining epigenetic therapy with traditional treatment is expected to improve the therapeutic effect and treat drug-resistant prostate cancer more effectively. 7 Emerging Treatment Methods for Histone Modification 7.1 Development of epigenetic drugs: HDAC and methylation inhibitors The development of epigenetic drugs is very promising in the treatment of cancer through histone modification. For instance, scientists have conducted extensive research on histone deacetylase (HDAC) inhibitors. These inhibitors can acetyl histones, alter chromatin structure, and activate genes that inhibit tumor growth. It can prevent cancer cells from dividing, promote their death, and enhance the anti-cancer effects of other drugs. It is a very effective anti-cancer drug (Li and Seto, 2016; Ramaiah et al., 2021). Furthermore, inhibitors targeting histone methylation have also been developed. These drugs can alter the abnormal methylation states associated with cancer deterioration (Cheng et al., 2019; Neganova et al., 2020). Because epigenetic modifications can be reversed, these inhibitors are particularly suitable for treating diseases (Kelly et al., 2010). 7.2 Combination therapy for histone modification and traditional therapy Combining epigenetic drugs with traditional cancer treatment methods is a good way to improve the treatment effect. In clinical trials, HDAC inhibitors, when used in combination with DNA methyltransferase inhibitors and histone methyltransferase inhibitors, have shown good effects in the treatment of various cancers (Cheng et al., 2019; Ramaiah et al., 2021). The occurrence of prostate cancer is related to abnormal histone acetylation and methylation. Combining treatments targeting these modifications with conventional therapies can achieve better therapeutic effects (Sugiura et al., 2020). Moreover, the combination of epigenetic drugs with chemotherapy drugs and signal transduction inhibitors may also solve the problem of drug resistance in cancer cells and enable patients to recover better (Kelly et al., 2010; Szczepanek et al., 2023). 7.3 Clinical outcomes and challenges of prostate cancer treatment Epigenetic methods for the treatment of prostate cancer have achieved some good results, but there are also many problems. HDAC inhibitors can prevent tumor enlargement and improve the recovery chances of patients in the
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