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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
HDACs play a key role in the progression of cancers by promoting the expression and activity of oncogenes while down regulating the tumor suppressors (Figure 8.2) (Ropero and Esteller, 2007). Deregulated expression of HDACs induces the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), while promoting the secretion of various pro-inflammatory cytokines and growth factors in to the microenvironment, which subsequently promotes the growth of tumors (West and Johnstone, 2014). In addition, prior studies have reported mutations in HDACs (Kupis et al., 2016). For example, a truncating mutation of HDAC2 induced resistance to HDACis in cancer cells, suggesting the requirement of the assessment of HDAC2 mutational status before deciding on a treatment agent. Few other studies have shown that HDAC3 is associated with DNA damage control response, and inactivation of HDAC3 causes genomic instability (Bhaskara et al., 2010). Recently, mutations in HDAC4 have been identified at significant frequency in breast and colorectal cancers (Stark and Hayward, 2007). Similarly, mutations in SIRT2 (which acts as a tumor suppressor) contribute to genomic instability and tumorigenesis (Head et al., 2017). Therefore, HDACs are the key proteins involved in tumor initiation, progression and metastatic spread; hence, targeted inhibition of HDACs is likely to reduce tumor burden in cancer patients.
Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Signal transduction also depends on the controlled movement of signal transduction proteins within the cell. One of the most important transport events is the bidirectional shuttling (i.e. translocation) of signal transduction proteins between the cytosol and the nucleus. In some cases, such movement depends on the activation of a nuclear localisation signal or sequence (NLS) on a protein. NLSs are recognised by proteins that transport protein cargo through nuclear pores from the cytosol into the nucleus of a cell. Usually, the activation of NLS involves protein modification or a change in protein-protein interaction, which exposes the NLS. For example, NF-κB is bound to its inhibitor, IκB, when it is in the cytosol. This is because IκB masks the NLS of NF-κB, which prevents it from transiting into the nucleus. In a similar manner, binding of class IIa histone deacetylases (HDACs) with the chaperone protein 14-3-3 masks the NLS and exposes the nuclear export sequence (NES) resulting in nuclear export and cytosolic retention of HDAC4. Phosphorylation of three serine residues (Ser246, Ser467 and Ser632) plays a key role in modulating HDAC4 translocation by increasing 14-3-3 binding and leading to nuclear export and the de-repression of gene transcription.
The Role of Epigenetics in Skeletal Muscle Adaptations to Exercise and Exercise Training
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Emerging evidence suggests that histone modifications could also be an important epigenetic mechanism contributing to exercise-induced transcriptional responses in skeletal muscle. Global histone 3 acetylation at lysine 36 is increased immediately following 60 min of cycling in human skeletal muscle and is associated with the nuclear export of the class IIa histone deacetylases (HDACs) (41). This sub-family of HDACs does not possess activity against acetylated lysine, but acts as scaffolds to recruit transcriptional co-repressors and other HDAC isoforms to specific transcription factors (18), such as MEF2 (45). The phosphorylation-dependent nuclear export of the class IIa HDACs disrupts this transcriptional co-repressor complex, resulting in transcription factor–specific gene expression responses (45). The importance of disrupting this co-repressor complex for the transcriptional response to exercise has been highlighted in a recent study (19). Skeletal muscle expression of HDAC4 and HDAC5 mutants that have impaired recruitment of the co-repressor complex results in an exercise-like transcriptional response and enhanced capacity for lipid oxidation (19). Phosphorylation of the class IIa HDACs appears to be regulated by a number of kinases, including the AMP-activated protein kinase (AMPK) (44), the calcium/calmodulin-dependent protein kinase II (CaMKII), and protein kinase D (PKD) (12), in a redundant fashion (43). These studies delineate important signalling pathways by which exercise can induce specific transcriptional responses through epigenetic mechanisms.
Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.
Published in Expert Opinion on Therapeutic Targets, 2019
John W. Hanrahan, Yukiko Sato, Graeme W. Carlile, Gregor Jansen, Jason C. Young, David Y. Thomas
The peripheral quality control system contains many potential therapeutic targets (see [12,84]). CHIP directs mutant CFTR from the cell surface to lysosomes for degradation and it is assisted by HSP90α, HSC70, DNAJA1, DNAJB2, DNAJC7, BAG1, HOP and AHA1 [85]. However, HSC70 and its co-chaperone DNAJA2, and HSP90 together with p23/PTGES also help maintain the activity of mutant CFTR [86]. Thus, targeting of HSC70 and HSP90 to slow CFTR internalization could be counterproductive if it results in inactive channels. The effects of pharmacologically inhibiting HSC70/HSP70 are complex due to the range of inhibitor mechanisms and the roles of chaperones in both folding and degradation. One early sulfoglycolipid inhibitor, adaSGC, increases F508del-CFTR trafficking at permissive low temperatures [87]. Apoptozole, an ATP competitor, was reported to increase F508del-CFTR trafficking and decrease its ERAD [88]. Pifithrin-μ/2-phenylethynesulphonamide (PES) targets HSC70/HSP70 substrate binding and along with apoptozole and the HSP90 inhibitor geldanamycin impairs the stability of mutant channels at the cell surface [86]. Small molecules that selectively ablate the role of chaperones in CFTR degradation have not yet been found. Interestingly, modification of HSP70 by the acetyltransferase ARD1 and the deacetylase HDAC4, respectively, block and favor association with CHIP, and this may be one mode of action of HDAC inhibitors [77].
Pro-resolving lipid mediators as therapeutic leads for cardiovascular diseases
Published in Expert Opinion on Therapeutic Targets, 2019
Emerging evidences show that lipid mediators might involve in multiple signaling pathways in cardiovascular diseases, such as NF-κB, VEGF, Nrf2/HO-1, MAPK, Na+-K+-ATPase and so on. Importantly, 15d-PGJ2 is well recognized and studied as a natural PPARγ agonist. Along with our network pharmacological and bioinflammatic analysis, we discover lipid mediators possibly as HDAC4 and FAAH inhibitors. HDAC4, as a member of histonedeacetylases, regulates epigenetic. Recent studies demonstrate that overexpressing HDAC4 accelerates myocardial ischemia-reperfusion injury, while HDAC inhibition promotes myocardial repairs. However, there are few HDAC inhibitors except valproic acid used to treat myocardial infarction so far [151]. Thus, searching for new HDAC4 inhibitors from lipid mediators, and evaluating the protective effects of these lipid mediators on myocardial ischemia-reperfusion injury are of great significance and become a research focus in the coming years. FAAH is another key therapeutic target for cardiovascular disease. Nowadays, several FAAH inhibitors (PF-04457845, BIA 10–2474) missed targets and produce side effects in the clinical study [152]. It is urgent to find novel-specific FAAH inhibitors without adverse effects. Lipid mediators might provide a natural and non-immunosuppressive molecular library to screen FAAH inhibitors. Collectively, lipid mediators can act as a potential resource for drug discovery in cardiovascular diseases.
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
Yet another important cytoplasmic target of HDAC4 concerning epilepsy is the Activating Transcription Factor 4 (ATF4). Besides its role in learning and memory, Corona et al. have reported the role of ATF4 in regulating neuronal excitability by modulating the trafficking of GABAB receptors (GABABRs) which makes it an interesting candidate for epilepsy [52]. ATF4 can also contribute to the process of epileptogenesis as it is responsible for neuronal apoptosis in response to endoplasmic reticulum (ER) stress. HDAC4 is responsible for interacting with ATF4 and retaining it in the cytoplasm inhibiting its transcriptional activity [53].