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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Transcription in cells is controlled by a number of mechanisms, including the degree of acetylation of lysine residues in the histone N-terminal tails. This is controlled by two families of enzymes, known as histone acetyltransferases and histone deacetylases (HDACs), which dictate the pattern of histone acetylation and deacetylation associated with transcriptional activation and repression, respectively (see Figure 5.109).
The Opioid Epidemic
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Morphine also impacts epigenetic mechanisms that result in hyperalgesia and tolerance by changes in long-term gene expression in the pain system. Histone acetylation and deacetylation help to control gene expression. Histone acetyltransferase (HAT) enzymes transfer an acetyl group onto histones. The result is a more relaxed chromatin structure (euchromatin) and greater gene transcription. This relaxed structure can be “undone” by histone deacetylase (HDAC) transforming to a more condensed form (heterochromatin). Increasing morphine dose enhances the expression of acetylated histone H3 lysine9 (aceH3K9) in the dorsal spinal cord, which regulates the expression of dynorphin and brain-derived neurotrophic factor (BDNF).21 HAT inhibitors prior to morphine exposure (such as curcumin) have reduced the development of opioid-induced hyperalgesia.1,22 Conversely, HDAC inhibitor injections after morphine exposure prolong the morphine hyperalgesia and tolerance.22 Preventing the acetylation of histones or blocking BDNF or dynorphin may reduce hyperalgesia.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The above-mentioned hypomethylation promotes the malignant degeneration of cells due to favoring a reorganization of chromosomal sections. The most important mechanism of epigenetic regulation is the methylation of DNA by DNA-methyltransferases. It has been found that hypermethylation (methylation of cytosine residues of DNA) of gene-promoter regions, leading to transcriptional repression of tumor suppressor genes the protein products of which such as CDK-inhibitor 2A and RB1 (retinoblastoma protein) decelerate tumor progression, is a common feature of many cancers (Baylin and Jones, 2011). This also holds for global deacetylation. Histone deacetylases (HDACs) class I, II, and IV are Zn2+-dependent amidohydrolases removing an acetyl moiety from a lysine residue at the N-terminus of histone. Class III HDACs (sirturins) are NAD+-dependent. The catalytic action of HDACs enables the histones to wrap the DNA more tightly whereas acetylation of histones by acetyl transferases (HATs) transferring an acetyl group from acetyl-CoA to form ε-N-acetyl lysine normally results in an increase in gene expression, e.g., that of the tumor suppressor p53. Various HAT families are known that differ from each other in their reaction mechanism. The equilibrium of histone acetylation and deacetylation is important for a proper modulation of chromatin topology and regulation of gene transcription. For an excellent review of exploiting the epigenome to control cancer-promoting gene-expression programs, see Brien et al. (2016).
Targeted drug therapy in non-small cell lung cancer: Clinical significance and possible solutions-Part I
Published in Expert Opinion on Drug Delivery, 2021
Archana Upadhya, Khushwant S. Yadav, Ambikanandan Misra
The taxanes (paclitaxel and docetaxel) inhibit depolymerization of microtubules thus changing microtubule dynamics and eventually causing cell death by blocking cellular mitosis [115]. The factors for resistance to taxane-based therapy are increased expression of class III tubulin [116] and its mutations, up-regulation of histone deacetylase 6 (HDAC 6) and impairment of the mitotic spindle checkpoint [111]. The function of the mitotic spindle checkpoint is to block the segregation of abnormal chromosomes. In lung cancer cells, the mitotic spindle checkpoint is dysregulated [79,111]. The taxanes bind specifically to class I β tubulin isoform which differs in critical binding residues from the class III β isoform [117]. Class III β – tubulin is one of the β isoforms that heterodimerize with α subunits to form microtubules essential for cell division [117] and its high expression correlates with poor survival in NSCLC [118]. Histone acetylation and deacetylation regulate transcription of DNA segments. Histone acetylases (HATs) promote transcription while histone deacetylases (HDACs) inhibit transcription by making DNA inaccessible. Histone deacetylase six interacts with histone and non-histone substrates. Non – histone interactors are α-tubulin, contractin and heat shock protein 90 (Hsp90) which when modified by HDAC6 can promote cell proliferation, metastasis, invasion, and mitosis [119].
Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Susanna Nencetti, Doretta Cuffaro, Elisa Nuti, Lidia Ciccone, Armando Rossello, Marina Fabbi, Flavio Ballante, Gabriella Ortore, Grazia Carbotti, Francesco Campelli, Irene Banti, Rosaria Gangemi, Garland R. Marshall, Elisabetta Orlandini
In the past years, a group of enzymes involved in the epigenetic regulation of gene expression, histone deacetylases (HDACs), have generated increasing interest as potential therapeutic targets for UM4–6. HDACs remove the acetyl groups from histone lysine residues from diverse protein targets, resulting in a condensed chromatin structure that downregulates gene expression, also of tumour suppressor genes7. The status of histone acetylation depends on the balance between histone acetylation and deacetylation, induced by histone acetyltransferases (HATs), and HDACs, respectively. Increasing evidence suggests that the alteration of HAT/HDAC activity is present in cancer8. In mammalians, 18 different HDACs have been identified and divided into four classes (Class I, Class II, Class III, and Class IV) based on their sequence homology to yeast proteins domain organisation and subcellular localisation. Class I (subtypes 1,2,3,8), II (subtypes 4,5,6,7,9,10), and IV (subtype 11)9 HDACs are zinc-dependent enzymes, while Class III HDACs (SIRTs 1–7) require the cofactor NAD+ to express their activity. Class I can generally be detected in the nucleus and is ubiquitously expressed.
Resveratrol inhibits ACHN cells via regulation of histone acetylation
Published in Pharmaceutical Biology, 2020
Lili Dai, Lingyan Chen, Wenjing Wang, Peizheng Lin
Studies have focussed on histone deacetylation, an important epigenetic modification involved in the development of many types of malignant tumours, including renal cell carcinoma, leukaemia, prostate cancer, lung cancer and colon cancer (Marti et al. 2012; Chiu et al. 2013). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are enzymes that, respectively, control histone acetylation and deacetylation and play a pivotal role in the regulation of chromatin structure and gene expression. Breaking the balance between HAT and HDAC would directly cause the occurrence and development of cancer. In addition to this, immunohistochemical evaluation and microarray analysis provide evidence that histone acetylation is a common change in RCC (Kanao et al. 2008; Mosashvilli et al. 2010; De Vito et al. 2018). Histone acetylation may therefore be a potential therapeutic target for RCC.