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Food Interactions, Sirtuins, Genes, Homeostasis, and General Discussion
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
The sirtuins are a family of proteins (enzymes) that act predominantly as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, which require nicotinamide adenine dinucleotide (NAD+) as an essential co-factor (63, 66–70). Acetylation and deacetylation are two important biochemical reactions to regulate the activity of proteins. All sirtuins require the coenzyme nicotinamide adenine dinucleotide (NAD+) for their deacetylase or ADP-ribosyl transferase activity, linking their function tightly to cellular energy levels (66–70).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Conversely, Histone Deacetylase Enzymes (HDACs) remove the acetyl groups, leading to condensed and transcriptionally silenced chromatin. This reversible modification of the terminal tails of core histones represents the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. Deacetylation by HDACs removes these charge-neutralizing acetyl groups, thus allowing the histone protein to have an increased affinity for DNA, leading to transcriptional repression (e.g., chromatin “closing”). HATs and HDACs do not work independently but exist in multiprotein complexes, where they work together to maintain fine control of transcriptional activation and repression. HDAC inhibitors interfere with this action, leading to hyper-acetylation of histone proteins and enhanced gene expression. There is also growing evidence that HDAC enzymes play a role in other biological processes, such as microtubule structure and function, and the cell cycle.
Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
Inhibitors of histone acetyltransferases also ameliorate the premature aging phenotypes of progeroid mice and extend their lifespan (Krishnan et al. 2011). Acetylation of the hippocampal histones, such as H2B, H3, and H4, were transiently increased in normal mice during learning processes, suggesting that histone acetylation is essential for memory consolidation (reviewed in Lu et al. 2015). Restoration of physiological H4 acetylation, through administration of HDACi, prevents the manifestation of age-associated memory impairment in mice (Peleg et al. 2010), indicating that reversion of epigenetic changes may have neuroprotective effects. Decreased H3K27 acetylation at regulatory regions of synaptic plasticity, as well as in immune response genes in the p25 transgenic model of AD, was found to correspond to the changes in transcription (Gjoneska et al. 2015). Whereas histone acetylation shows an overall decrease in the aged mice, the application of HDAC inhibitors reverses such decreases in the global histone acetylation and improves the memory deficits in vivo (Chuang et al. 2009; Gräff et al. 2012; Walker et al. 2013).
Histone deacetylase inhibitors as a potential new treatment for psoriatic disease and other inflammatory conditions
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Jehan Mohammad Nazri, Katerina Oikonomopoulou, Elvin D. de Araujo, Dziyana Kraskouskaya, Patrick T. Gunning, Vinod Chandran
Regardless, given the possibility of genes and proteins as well as histones and non-histones that can be affected by HDACs, it has become clear that HDACs play an essential role in regulating human health. By the same token, abnormal HDAC activity or expression may also lead to disease development. In fact, in cancer, a widely studied field for HDACs (and HDAC inhibitors), global loss of monoacetylated (and trimethylated) histone H4 is an important event [135,136]. Cancer has also been linked to overexpression of HDAC proteins, somatic HDAC mutations, as well as aberrant recruitment of HDACs to specific promoters [115]. HDACs may also mediate cancer progression through deacetylation of important non-histone substrates like oncogenes, tumor suppressors, and other proteins that regulate tumor development [115,123]. Abnormal patterns of HDAC expression and/or function in other diseases like psoriasis have also emerged and will be discussed later.
Epigenetic regulatory mechanisms of histone acetylation in the treatment of cutaneous squamous cell carcinoma
Published in Expert Opinion on Therapeutic Targets, 2021
Tejas P. Joshi, Morgan A. Farr, Daniel J. Lewis
Withstrong interest, we read the review article, ‘LSD1: a viable therapeutic target in cutaneous squamous cell carcinoma’ by Egolf and Capell. The authors emphasize the development of inhibitors targeting LSD1, a histone demethylase, in treating pre-malignant and malignant cutaneous squamous cell carcinoma (cSCC). The development of novel, effective therapies is significant, as cSCC is the second common malignancy [1]. In addition to histone demethylase inhibitors, histone deacetylase (HDAC) inhibitors have the potential as epigenome-targeted therapy to treat cSCC. HDACs act in balance with histone acetyltransferases (HATs) in regulating cell migration, proliferation, and apoptosis. Imbalances may lead to over- or under-expression of genes that produce increased tumor activity [2]. HDAC inhibitors reduce tumorigenesis by blocking HDAC activity and creating more relaxed chromatin structure, thus inducing gene expression by inhibiting deacetylation of transcription factors. Herein, we suggest that HDAC inhibitors merit further study as a therapy for cSCC [3].
Non-histone substrates of histone deacetylases as potential therapeutic targets in epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Sonali Kumar, Diksha Attrish, Arpna Srivastava, Jyotirmoy Banerjee, Manjari Tripathi, P Sarat Chandra, Aparna Banerjee Dixit
A complementary biochemical technology such as affinity purification followed by protein identification using mass spectrometry (MS) can be applied to discover the whole spectrum of proteins interacting with the specific HDAC. Over the last two decades, increasing research effort in academia and industry has focused to identify the molecular target that can selectively target disease-specific mechanisms or pathways. In particular, understanding how HDACs and its non-histone substrates engage and communicate will allow us to understand the mechanism of disease and provide several potential therapeutic targets. Apart from identifying the interacting partners of HDACs for better therapeutic strategies, there is also a need to understand the complex mechanism of acetylation and deacetylation as it can play a critical role in the development of the disease and its functional consequences can be as broad as the targets. Research efforts should also be put into determining how the acetylation status of non-histone substrates affects the interaction, localization, and degradation of proteins.