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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
SCFAs are another class of HDAC inhibitors known to impede cancer cell growth (Anantharaju et al., 2017a). SCFAs are produced in humans as a result of gut-microbial activity on dietary fiber components. The most predominantly produced SCFAs are acetate, propionate and butyrate (den Besten et al., 2013). Several studies have shown that butyrate, but not propionate, inhibit HDAC activity more effectively (Silva et al., 2018). Currently, butyrate is being clinically evaluated as an antineoplastic agent not only due to its ability to induce cell cycle arrest, differentiation, and/or apoptosis in cancer cells, but also due to its favorable safety profile in humans (Chen et al., 2003). Mechanistically, gut microbiota–derived butyrate inhibits Class I HDACs, thereby promoting crotonylation of histone-3 (H3) at lysine 18 residue, which subsequently regulates the expression of several genes involved in cells’ proliferation and survival (Fellows et al., 2018). Structure-inhibition relationship (SIR) studies further confirm that butyrate more specifically inhibits Class I HDACs, in particular HDAC3 compared to Class II HDACs such as HDAC7 (Steliou et al., 2012).
Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
Amplifiers are modulators that increase CFTR expression (Mijnders, Kleizen, and Braakman, 2017). PTI-428 is an amplifier that increases the amount of CFTR mRNA and protein loaded on to the endoplasmic reticulum. The amplifier is usually combined, either with a corrector or potentiator modulator. These modulators play an important role in the treatment of most CFTR class mutations except class I mutation, owing to a premature termination codon mutation that leads to defective protein production. To overcome this drawback, a combination of an aminoglycoside antibiotic, like gentamicin or tobramycin, and PTC124 (Ataluren) is employed (Almughem et al., 2020). A small molecule HDAC7 inhibitor SAHA1 not only amplifies F508del-CFTR expression, but also promotes significant transport of F508del-CFTR to the cell surface by reshaping CFTR’s proteostasis network (Mijnders, Kleizen, and Braakman, 2017).
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
DNA methylation patterns in human solid tissues were found to be dependent both on tissue and age [23]. A rather distinct correlation between age and methylation was observed, with loci in CGIs gaining methylation with age and loci not in CGIs losing it. This pattern was consistent across tissues and in blood-derived DNA. Gene loci that earlier have been reported to be associated with aging, ESR1, GSTP1, IGF2, MGMT, MYOD1, RARB, and RASSF1, displayed significant methylation alterations (mainly increases) with age. Loci in epigenetic regulatory genes (LAMB1, DNMT1, DNMT3B, HDAC1, and HDAC7), telomere maintenance genes (TERT, ERCC1, and RAD50), and a premature aging syndrome gene (WRN), all showed age-related methylation alterations. In contrast to the predominantly increased age-associated methylation at other gene loci, there was a significant age-related decrease in CpG methylation of DNMT3B that, unlike the vast majority of hypermethylated CpG loci tested, was not located in a CGI.
Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men
Published in Endocrine Research, 2020
Christa Broholm, Rasmus Ribel-Madsen, Line Hjort, Anders Henrik Olsson, Juliane Maria Dorothee Ahlers, Ninna Schiøler Hansen, Maren Schrölkamp, Linn Gillberg, Alexander Perfilyev, Petr Volkov, Charlotte Ling, Sine W. Jørgensen, Brynjulf Mortensen, Janne Hingst, Jørgen Wojtaszewski, Camilla Scheele, Charlotte Brøns, Bente Klarlund Pedersen, Allan Vaag
HDAC7 expression was down-regulated in LBW. Histone deacetylase 7, encoded by HDAC7, plays a critical role in transcriptional regulation. Impaired histone deacetylase function has primarily been reported in the field of cancer research43, but as a transcriptional regulator is also a candidate for dysregulation of myogenesis. Hence, in a C2C12 mouse cell line a role of HDAC7 in myocyte differentiation has been demonstrated through interaction with myocyte enhancer factor-2, which regulates myosin 2 expression.44 In our human myoblasts siRNA silencing of HDAC7 resulted in tenuous myofiber formation. Accordingly, myogenin protein was also downregulated relative to the total protein amount. This phenotype is consistent with the impaired myogenic potential in LBW individuals.15 The silencing of HDAC7 also led to decreased glucose uptake. A recent genome-wide study of human pancreatic islets pointed to HDAC7 as a candidate gene showing decreased methylation and increased expression in type 2 diabetes.45 In a rat beta-cell line HDAC7 overexpression impaired insulin secretion and mitochondrial function potentially through interaction with the type 2 diabetes gene TCF7L.246 Hence, HDAC7 represents an interesting candidate gene for type 2 diabetes risk in different tissues and at different stages of cell maturation.
Cross-talk between energy metabolism and epigenetics during temperature stress response in C2C12 myoblasts
Published in International Journal of Hyperthermia, 2019
Basavaraj Sajjanar, Puntita Siengdee, Nares Trakooljul, Xuan Liu, Claudia Kalbe, Klaus Wimmers, Siriluck Ponsuksili
Histone acetyl transferases (HATs), responsible for acetylation of histone tails, include the three major subtypes p300, Gcn5 and Cbp. The overall expression levels of HATs were increased in response to rising temperatures. Noteworthy, the Gcn5 subtype was significantly upregulated in high thermal stress (41 °C) and downregulated by low temperature stress (35 °C), compared to normothermic condition (Figure 8). Histone deacetylases (HDACs) are responsible for removal of acetyl group from the tails of histones belonging to class I HDACs (Hdac1, Hdac2, Hdac3 and Hdac8) and class II HDACs (Hdac4, Hdac5, Hdac6, Hdac7 and Hdac9). Under low-temperature conditions (35 °C), Hdac2 and Hdac8 (Class I) as well as Hdac4 and Hdac5 (Class II), were significantly downregulated relative to the control cells, while Hdac6 and Hdac7 tended to be upregulated, albeit the latter changes did not reach statistical significance. Hdac8 (Class I) and Hdac7 (Class II) were significantly downregulated in both high-temperature conditions tested (39 °C and 41 °C) (Figure 9). In contrast, Hdac9 was upregulated in the high temperature conditions.
HDAC inhibitors: a 2013–2017 patent survey
Published in Expert Opinion on Therapeutic Patents, 2018
Micaela Faria Freitas, Muriel Cuendet, Philippe Bertrand
The future in the field should be the production of selective inhibitors for the other class II HDACs, such as HDAC7 whose specific activity is demonstrated in immune diseases and bone pathologies. Recent work and some of the patents presented here also highlighted the emerging interest for compounds having a dual activity, by combining HDAC inhibitor scaffolds to structures belonging to another therapeutic class or within the epigenetic target inhibitor classes. This strategy is illustrated by 70% of the clinical trials found in the last four years. In addition, compounds blocking the catalytic activity could also be designed to block protein–protein interaction involving HDACs. With the numerous metalloenzymes used as targets for therapeutic applications, an important challenge to solve in the near future with a third-generation HDAC inhibitors is the replacement of current hydroxamic acids by other ZBG that could bind only the zinc atom of HDACs at the nanomolar level.