Cancer Genetics and Epigenetics, 2025, Vol.13, No.2, 77-89 http://medscipublisher.com/index.php/cge 82 a type of HDACi that has been studied extensively. Clinical trials have shown that it can exhibit strong anti-cancer effects by selectively altering gene expression, such as inducing the expression of p21 (WAF1), a protein that can prevent the cell division cycle of cancer cells (Gui et al., 2004). In addition, the use of HDACi treatment can also increase the level of histone acetylation and affect the gene expression related to proteins such as BRD4, with an effect similar to that of inhibiting the function of bromine-domain proteins (Slaughter et al., 2021). The therapeutic advantages of HDACi are not only reflected in its use alone. The combined use of HDACi with other anti-cancer drugs can produce a synergistic effect, which can not only improve the therapeutic effect, reduce tumor drug resistance, but also reduce drug side effects. These research results indicate that HDACs is an important target for the treatment of prostate cancer, and HDACi also has great potential to optimize the existing treatment regimens (Li et al., 2020; Pramanik et al., 2022). 5 Crosstalk of Five Histone Modifications in Prostate Cancer 5.1 Synergistic effects among different histone modifications Histone modifications do not function alone; there are complex interactions among them that can jointly affect gene expression and chromatin structure. For example, after the acetylation of the lysine 16 site of histone H4 (H4K16ac), the methyltransferase (Dot1) of lysine 79 of histone H3 will be activated. After this enzyme is activated, it will trigger other histone modifications and ultimately promote gene transcription (Purnell, 2021). This mutual influence among histones indicates that one modification can make another modification more likely to occur, thereby triggering a series of epigenetic changes and having a significant impact on gene expression. There is a mutual inhibitory relationship between citrullination at site 26 of arginine (H3R26) and methylation at site 27 of lysine (H3K27) in histone H3. The citrullination of H3R26 prevents the methylation of H3K27, and vice versa. The effects of these two modifications on gene expression are exactly opposite. During the development of cancer, this interaction is crucial because these modification changes may promote the continuous growth of cancer cells (Clancy et al., 2017). 5.2 Chromatin remodeling and transcriptional regulation through histone crosstalk The changes in chromatin structure are an important link in controlling gene expression, and histone modification plays a core role in this process. For patients with prostate cancer, abnormal expression of androgen receptors (AR) can make the chromatin structure loose, making it easier for transcription factors to bind to it and thereby accelerating the deterioration of cancer. Proteins with bromine domains can recognize acetylation markers on histones. In patients with castration-resistant prostate cancer (CRPC), the excessive amount of such proteins leads to an increasingly intractable condition (Urbanucci et al., 2017). When histone variants like H3.3 bind to chromatin, cancer cells are more likely to acquire invasion and metastasis capabilities. This binding process is regulated by histone chaperone proteins and is a necessary condition for activating those genes related to poor prognosis and cancer cell metastasis (Gomes et al., 2019). These research results indicate that the interactions among histone modifications are significant for chromatin structure alterations and also affect the expression regulation of prostate cancer-related genes. 5.3 Role in the invasion and progression of prostate cancer The interaction among histone modifications is not only crucial for gene regulation, but also plays an important role in the deterioration and metastasis of prostate cancer. For instance, after the lysine 120 site of histone H2B undergoes monoubiquitination (H2Bub1), it makes chromatin easier to be "read" and promotes gene transcription. These processes are essential for the growth of cancer cells and the deterioration of tumors. If the modification H2Bub1 is absent, the recovery of patients with various cancers, including prostate cancer, is poor, indicating that it has an inhibitory effect on tumors (Marsh et al., 2020). Abnormalities in the distribution and overall level of histone modifications, such as changes in the positions of nucleosomes at gene promoters and enhancers, can cause the genes that originally inhibit tumors to fail to function, while the genes that promote tumor growth are activated. Androgen receptors also cause chromosomes to form
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