Cancer Genetics and Epigenetics, 2025, Vol.13, No.2, 77-89 http://medscipublisher.com/index.php/cge 83 special circular structures, which trigger gene fusion. This is also a way in which histone modification promotes the development of prostate cancer (Chen et al., 2010). 6 Histone Modification and Drug Resistance in Prostate Cancer 6.1 The role of histone modification in the occurrence of androgen resistance Histone modification has a significant impact on androgen resistance in prostate cancer. The signals sent by androgen receptors are crucial for the growth and survival of prostate cancer cells. Even if cancer cells have developed resistance to androgen deprivation therapy, this signal remains important. Whether it is hormone-sensitive prostate cancer or castration-resistant prostate cancer, histone deacetylase is indispensable for androgen receptors to function. Histone deacetylase inhibitors such as SAHA and LBH589 have been proven to prevent the activation of androgen receptor regulatory genes, especially those that fuse with members of the ETS family, a situation that is common in prostate cancer. Inhibitors reduce the number and activity of androgen receptors by inhibiting the activity of androgen receptors and interfering with the combination of activating proteins and RNA polymerase II complexes on the enhancer of the target gene (Welsbie et al., 2009). In addition, histone methylation, especially the modifications initiated by enzymes such as EZH2, can inhibit the expression of androgen receptors, promote the expression of genes related to neuroendocrine, and facilitate the formation of castration-resistant prostate cancer (Figure 3) (Imamura et al., 2023). Figure 3 Markers of Phenotypic Plasticity in Prostate Cancer (Adapted from Imamura et al., 2023) Image caption: This figure illustrates the phenotypic transition of prostate cancer from androgen-dependent adenocarcinoma (Adenocarcinoma) to castration-resistant prostate cancer (CRPC) and finally to neuroendocrine prostate cancer (NEPC). The intermediate states represent changes in cancer cell phenotypic plasticity. Genetic mutations such as ETS fusion, SPOP, TP53, AR, and epigenetic alterations like DNA methylation, chromatin relaxation, and AR methylation drive these phenotypic transitions. The final phenotypic shift not only increases cancer metastasis potential but also alters androgen dependence (Adapted from Imamura et al., 2023) Imamura et al. (2023) found that prostate cancer can alter its own characteristics, which is the key to its deterioration and the development of drug resistance. After androgen deprivation therapy, prostate cancer can progress from androgen-dependent adenocarcinoma to castration-resistant prostate cancer, and may even transform into more difficult-to-treat neuroendocrine prostate cancer. This transformation process not only involves gene mutations, but is also accompanied by epigenetic regulatory changes such as DNA methylation and alterations in chromatin structure. These findings bring opportunities for the development of new anti-cancer therapies.
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