The Opioid Epidemic
Sahar Swidan, Matthew Bennett in 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.
Micronutrients for Improved Management of Huntington’s Disease
Kedar N. Prasad in Micronutrients in Health and Disease, 2019
Histone acetylation and deacetylation regulate gene transcription. Acetylation of histone at specific residues increases transcription of genes, whereas deacetylation of histones suppresses transcriptional activity that has been implicated in the pathogenesis of HD. In animal models of HD, expression of HD gene decreases the activity of histone acetyl transferase. This enzyme is responsible for deacetylation of histone leading to inhibition of the transcriptional activity that causes neurodegeneration in the brain. Inhibitors of histone deacetylase (HDAC) produce some beneficial effects in several animal models of HD35; however, their therapeutic value is limited by their toxicity. Chronic oral administration of a novel pimelic diphenylamide HDAC inhibitor, HDACi 4b, at the beginning and after the onset of motor deficits, significantly improved motor performance, overall appearance, and body weight in a transgenic HD mice model. These changes were associated with reduction in striatal atrophy and brain shrinkage. Alterations in gene expression caused by HD protein were prevented by the treatment with HDACi 4b.36
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Peter Grunwald in 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).
New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia
Published in Expert Opinion on Investigational Drugs, 2019
Fabio Penna, Paola Costelli
Histone acetylation and deacetylation result in increased or decreased cell transcriptional activity, respectively. Such balance mainly depends on the activity of two classes of enzymes, namely histone acetyltransferases (HATs) and HDACs [30]. In addition to histones, HDACs and HATs can also act on non-histone proteins. As an example, the cellular localization (activation/inactivation) of transcription factors, such as Signal Transducer and Activator of Transcription 1 (STAT1), Nuclear Factor-κB (NF-κB), p53, and FOXO can be affected by acetylation of specific lysine residues. Not only, the acetylation state can modulate protein stability, for instance by inhibiting their ubiquitylation and subsequent degradation by the proteasome. Three groups of HATs [31] and 18 HDACs, organized into four classes (I-IV), have been described so far (Table 1), based on structure, function, and phylogeny. Class I, II, and IV HDACs are considered as ‘classical’ Zn2+-dependent HDACs, while class III HDACs (sirtuins; SIRT) use NAD+ as a cofactor. HDACs included into class I and class IV have a nuclear localization, class IIa HDACs mainly reside in the cytoplasm and class IIb HDACs can be found both in the nucleus and in the cytoplasm, shuttling between the two cell compartments. Class III HDACs can be found in both the nucleus and cytoplasm, but also in mitochondria [31,32].
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].
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.
Related Knowledge Centers
- Acetylation
- Enzyme
- Histone
- Histone Acetyltransferase
- Histone Deacetylase
- Lysine
- N-Terminus
- Nucleosome
- Regulation of Gene Expression
- Acetyl-Coa