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Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, Colum P. Walsh
Acetyl-CoA is involved in the transfer of an acetyl group to lysine amino acids on the N-terminal tails of histone to yield acetylation (Martinez-Reynes and Chandel, 2020; Vanzan et al., 2017). Acetylation occurs on each of the four histones via HAT enzymes, and HATs can be sensitive to fluxes in intracellular acetyl-CoA concentration (Kaelin and McKnight, 2013; Wong et al., 2017). Histone acetylation regulates gene transcription. For example, acetylation (i.e. H3K9ac, H3K27ac) at specific gene loci is implicated in transcriptional activation by opening chromatin structure, through a combination of (1) histone acetylation neutralising their positive charge which may weaken the interaction of the nucleosome with the DNA, leading to the opening of chromatin and active transcription and (2) histone acetylation acting as a docking station for the recruitment of transcription regulators (Vanzan et al., 2017; Wang et al., 2018; Davison et al., 2021).
Emerging Highlights on Natural Prodrug Molecules with Multifarious Therapeutic Perspectives
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Mojabir Hussen Ansari, Vaibhav Shende, Debarshi Kar Mahapatra
Romidepsin is a bicyclic depsipeptide that was first isolated from a Gram-negative rod-shaped single polar flagellum bacteria Chromobacterium violaceum.16 In early 1990s, romidepsin remained an important fermentation product for treating tumor (histone deacetylase class-I inhibitor; however, the mechanism is not fully known) forms such as glioblastoma, leukemia, lymphoma, myeloma, and breast, colorectal, gastrointestinal, lung, ovarian, pancreatic, and prostate cancer and also for treating the microbial infections.17 It is a prodrug that requires a reduction of its disulfide bonds to activate its less stable form. Histone acetyltransferases and histone deacetylases control histone acetylation by the way of direct addition of acetyl groups to the lysine residues within the amino-terminal histone tails, which neutralizes the part of the protein and relaxes the chromatin structure.18 Romidepsin is also classified as an epigenetic agent that introduces stable genetic changes by interfering with the gene expression and their function, without any corresponding changes in the DNA sequence.19 In recent years, small molecules of histone deacetylase (HDAC) inhibitors have owned the position of strong anticancer agents, many of which are now FDA approved anticancer agents, which have challenged the position of romidepsin.20
Introduction to Cancer
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Histone acetylation and de-acetylation also play a role in epigenetic control by modulating chromatin condensation and transcription. These dynamic processes are regulated by enzymes known as histone acetyltransferases and their counterparts, the histone de-acetylases. The equilibrium between them can be modified by exogenous influences known as epigenetic modulators, which can modify methylation or acetylation and thus change the phenotypes of cells epigenetically, without their DNA sequences being altered.
Advances in Hodgkin’s lymphoma pharmacotherapy: a focus on histone deacetylase inhibitors
Published in Expert Opinion on Pharmacotherapy, 2023
Thuy Ho, Cara Coleman, Palak Shah, Victor Yazbeck
Carcinogenesis is not only driven by genetic mutations but also by post-transcriptional modifications, which are heritable and therefore propagate through clonal cell lines [16]. Epigenetic regulation changes the expression of genes without altering the DNA sequence by various chemical processes, such as methylation, acetylation, phosphorylation, ubiquitylation, and sumoylation, at the level of histones [17]. Histones are protein octamers around which DNA is wrapped, forming nucleosomes that combine to produce chromatin [18]. Histone tails protrude from the nucleosome and undergo the aforementioned chemical modifications, creating a histone code, which alters the chromatin structure and subsequently many cellular functions. Histone acetylation is a reversible process, mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs catalyze the removal of acetyl groups from specific arginine and lysine residues on histone tails. Acetylated chromatin has a relaxed structure that is favorable for gene expression by enabling binding of transcription factors, whereas deacetylated chromatin has a closed structure, which supports transcription repression. Altered activity of HATs and HDACs leads to an imbalance of chromatin modifications and resultant expression of oncogenes. HDACs also play a role in regulating the acetylation of other key survival, non-histone proteins, which affect mRNA splicing, translation, and stability, as well as protein–protein interactions. Among the proteins that HDACs have been shown to modulate are p53, NFKB, and tubulin [18,19].
DNA methyltransferase inhibitors increase NOD-like receptor activity and expression in a monocytic cell line
Published in Immunopharmacology and Immunotoxicology, 2022
Claire L. Feerick, Declan P. McKernan
DNA methylation and histone acetylation are the best-characterized contributors to the epigenome [17,18] and so are investigated here. DNA methylation, catalyzed by DNA methyltransferase enzymes, involves the addition of a methyl group onto cytosine residues, forming 5-methylcytosine [19]. It is generally accepted that methylation of cytosines in CpG dinucleotides-rich regions, referred to as ‘CpG islands,’ within the transcriptional start sites (TSSs) silences the downstream gene [17]. Histone acetylation is the addition of acetyl groups to lysine residues in histone proteins thereby neutralizing lysine’s positive charge, reducing their affinity for surrounding DNA, and thereby relaxing the chromatin and accommodating expression of underlying genes [20]. Histone acetylation status is maintained by a balance in the activity of two enzymes; histone acetyltransferases (HATs) and histone deacetylases (HDACs) [21]. Drugs targeting epigenetic modifying enzymes have recently been used in the treatment of certain cancers but the full extent of their effects have not been studied [22–26]. Previous work from our group has shown that pharmacological and genetic inhibition of such enzymes affected TLR responses in intestinal epithelial cells [27]. We hypothesized that drugs targeting epigenetic modifications may regulate NOD1/2 expression and pro-inflammatory activity in a monocytic cell line.
Upregulation of OATP1A2 in human oesophageal squamous cell carcinoma cells via the HDAC6-GCN5/PCAF-H3K9Ac axis
Published in Xenobiotica, 2021
Xiaoli Zheng, Jian V. Zhang, Yanfeng Bai, Jiaqi Wang, Mingfeng Jiang, Su Zeng, Lvhua Wang
In cancer, epigenetic modifications are accomplished by DNA methylation, histone modifications and noncoding RNAs without changes in the DNA sequence. Alterations in epigenetic markers contribute to the inactivation of cellular factors that are involved in carcinogenesis (Liu et al. 2016; Buccarelli et al. 2020; Guerra et al. 2020). Histone acetylation is a dynamic epigenetic mediator that drives and maintains the malignant phenotype (Albrengues et al. 2015; Chen et al. 2019). Histone acetylation is mediated via histone acetyltransferases (HATs) and suppressed by histone deacetylases (HDACs). HATs such as p300/CBP, Tip60, MOZ/MORF, and GCN5/PCAF act as recruiters of acetyl groups during their interactions with HDAC complexes (Caslini et al. 2019; Wang et al. 2019). The study of epigenetic mechanism suggested that the expression of OATP1A2 was upregulated by the enrichment of H3K9Ac at promoter region of OATP1A2 in ESCC. In ESCC tumour tissues, loss of HDAC6 and enrichment of GCN5/PCAF induced H3K9Ac at the promoter region of OATP1A2. Therefore, the suppression of OATP1A2 by blocking upstream HDAC6-GCN5/PCAF-H3K9AC pathway may improve overall survival of patients with ESCC.