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  • The GSTP promoter region in PCA cells without


    The GSTP1 promoter region in PCA cells without or with reduced GSTP1 mRNA expression had a different histone modification pattern than BPH-1 cells with GSTP1 mRNA expression: the repressive histone modifications H3K9me3/H3K27me2 were distinctly increased and H3K27me3/H3K9me2 were slightly decreased in PCA cells; furthermore, activating histone marks (H3K4me3, H3K4me2 and H3K18ac) were decreased in PCA cells. Similarly, Stirzaker et al. reported repressive histone modifications (H3K9me2) at the GSTP1 promoter [11], whereas Okino et al. failed to detect repressive modifications (H3K9me2/3 and H3K27me2/3) at the GSTP1 promoter in LNCaP cells [19]. Our finding of accumulation of repressive histone marks is reasonable, and the discrepancy to earlier studies attributable to the use of different Cerulenin and a less sensitive, conventional PCR [11], [19]. The loss of activating modifications (H3Ac [11], [19]; H4Ac [19]; H3K4me2/3 [19]) in LNCaP cells was also reported earlier. Notably, global levels of H3K4me1, H3K9me2, H3K9me3, H3Ac, and H4Ac were significantly reduced in primary PCA compared to non-malignant prostate tissue [20]. Taken together, DNA methylation and histone modifications act together to induce an inactive chromatin pattern and to suppress gene expression. Previous studies investigated the HDAC inhibitor Trichostatin A; this compound increased the histone acetylation levels, but did not decrease GSTP1 DNA methylation and did not restore mRNA expression [5]. In comparison, the treatment of PCA cell lines with depsipeptide resulted in several changes: (i) as expected, the level of histone acetylation (H3K18Ac) increased; (ii) repressive histone modifications (H3K9me2/3 and H3K27me2/3) decreased; (iii) the levels of histone lysine methylation with activating effect (H3K4me2/3) decreased; and (iv) DNA was demethylated. As a consequence, GSTP1 mRNA levels increased several-fold in PCA cell lines. These findings indicate that depsipeptide influences various epigenetic functions:
    Introduction The cytosolic glutathione transferases (GSTs, EC. catalyze the conjugation of glutathione (γ-Glu-Cys-Gly, GSH) with a broad range of electrophilic substrates, including alkylating drugs (e.g. bendamustine, busulfan, chlorambucil, cisplatin) that are used in antineoplastic therapy, leading to their detoxification [[1], [2], [3], [4]]. Consequently, GSTs detoxifying ability although it protects and detoxify normal cells from deleterious compounds, unfortunately, also compromises the efficiency of antineoplastic therapy [[4], [5], [6]]. GSTs contribute two distinct roles in the development of cancer cell MDR phenomenon: either participate in direct detoxification of chemotherapeutics or by inhibiting the mitogen-activated protein (MAP) kinase pathway [7,8]. Extensive published work have demonstrated that hGSTP1-1, a particular GST overexpressed in most tumor cell lines and tumor tissues [5,6], forms a tight complex with c-Jun N-terminal kinase (JNK), thus preventing the apoptotic cascade related to the phosphorylation of c-Jun [[8], [9], [10]]. The development of chemotherapeutic resistant tumor cells, during cancer chemotherapy, remains an important problem that restricts the success of the therapeutic protocols and approaches since cancer cells do not respond appropriately to the antineoplastic drugs [6,11]. Hence, one of the proposed strategies to overcome multidrug resistance can be based on the use of specific GST inhibitors [3,[11], [12], [13], [14], [15], [16], [17]], that can function as regulatory agents in those cases where anticancer drugs are substrates for GSTs and therefore are detoxified through GSH catalysis. So far, the majority of GST-based drug design efforts are focused mainly on structure-guided approaches using heterocyclic compounds or GSH analogues as leaders for inhibitor design [3,[11], [12], [13], [14], [15], [16], [17]].