International Journal of Molecular Sciences

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Open AccessEditorial

Histone Acetyltransferase and Deacetylase Inhibitors—New Aspects and Developments

by Hany S. Ibrahim and Wolfgang Sippl

Int. J. Mol. Sci. 2023, 24(23), 16985; https://doi.org/10.3390/ijms242316985 - 30 Nov 2023

Cited by 1 | Viewed by 1285

Abstract

Epigenetic processes modulate gene transcription and genomic stability, ensuring proper cell development and differentiation [...] Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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14 pages, 3440 KiB

Open AccessArticle

HDAC1: An Essential and Conserved Member of the Diverse Zn²⁺-Dependent HDAC Family Driven by Divergent Selection Pressure

by Jing-Fang Yang, Le-Rong Shi, Ke-Chen Wang, Li-Long Huang, Yun-Shuang Deng, Mo-Xian Chen, Fang-Hao Wan and Zhong-Shi Zhou

Int. J. Mol. Sci. 2023, 24(23), 17072; https://doi.org/10.3390/ijms242317072 - 2 Dec 2023

Viewed by 1471

Abstract

Zn²⁺-dependent histone deacetylases (HDACs) are enzymes that regulate gene expression by removing acetyl groups from histone proteins. These enzymes are essential in all living systems, playing key roles in cancer treatment and as potential pesticide targets. Previous phylogenetic analyses of HDAC [...] Read more.

Zn²⁺-dependent histone deacetylases (HDACs) are enzymes that regulate gene expression by removing acetyl groups from histone proteins. These enzymes are essential in all living systems, playing key roles in cancer treatment and as potential pesticide targets. Previous phylogenetic analyses of HDAC in certain species have been published. However, their classification and evolutionary origins across biological kingdoms remain unclear, which limits our understanding of them. In this study, we collected the HDAC sequences from 1451 organisms and performed analyses. The HDACs are found to diverge into three classes and seven subclasses under divergent selection pressure. Most subclasses show species specificity, indicating that HDACs have evolved with high plasticity and diversification to adapt to different environmental conditions in different species. In contrast, HDAC1 and HDAC3, belonging to the oldest class, are conserved and crucial in major kingdoms of life, especially HDAC1. These findings lay the groundwork for the future application of HDACs. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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19 pages, 15837 KiB

Open AccessArticle

Continuous Fluorescent Sirtuin Activity Assay Based on Fatty Acylated Lysines

by Matthes Zessin, Marat Meleshin, Sebastian Hilscher, Cordelia Schiene-Fischer, Cyril Barinka, Manfred Jung and Mike Schutkowski

Int. J. Mol. Sci. 2023, 24(8), 7416; https://doi.org/10.3390/ijms24087416 - 18 Apr 2023

Cited by 4 | Viewed by 1923

Abstract

Lysine deacetylases, like histone deacetylases (HDACs) and sirtuins (SIRTs), are involved in many regulatory processes such as control of metabolic pathways, DNA repair, and stress responses. Besides robust deacetylase activity, sirtuin isoforms SIRT2 and SIRT3 also show demyristoylase activity. Interestingly, most of the [...] Read more.

Lysine deacetylases, like histone deacetylases (HDACs) and sirtuins (SIRTs), are involved in many regulatory processes such as control of metabolic pathways, DNA repair, and stress responses. Besides robust deacetylase activity, sirtuin isoforms SIRT2 and SIRT3 also show demyristoylase activity. Interestingly, most of the inhibitors described so far for SIRT2 are not active if myristoylated substrates are used. Activity assays with myristoylated substrates are either complex because of coupling to enzymatic reactions or time-consuming because of discontinuous assay formats. Here we describe sirtuin substrates enabling direct recording of fluorescence changes in a continuous format. Fluorescence of the fatty acylated substrate is different when compared to the deacylated peptide product. Additionally, the dynamic range of the assay could be improved by the addition of bovine serum albumin, which binds the fatty acylated substrate and quenches its fluorescence. The main advantage of the developed activity assay is the native myristoyl residue at the lysine side chain avoiding artifacts resulting from the modified fatty acyl residues used so far for direct fluorescence-based assays. Due to the extraordinary kinetic constants of the new substrates (K_M values in the low nM range, specificity constants between 175,000 and 697,000 M⁻¹s⁻¹) it was possible to reliably determine the IC₅₀ and K_i values for different inhibitors in the presence of only 50 pM of SIRT2 using different microtiter plate formats. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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15 pages, 5231 KiB

Open AccessArticle

Selective Targeting of Class I HDAC Reduces Microglial Inflammation in the Entorhinal Cortex of Young APP/PS1 Mice

by Chunyang Wang, Di Shen, Yingqiu Hu, Jie Chen, Jingyun Liu, Yufei Huang, Xuebin Yu, Haiying Chu, Chenghong Zhang, Liangwei Yin, Yi Liu and Haiying Ma

Int. J. Mol. Sci. 2023, 24(5), 4805; https://doi.org/10.3390/ijms24054805 - 2 Mar 2023

Cited by 8 | Viewed by 2641

Abstract

BG45 is a class Ⅰ histone deacetylase inhibitor (HDACI) with selectivity for HDAC3. Our previous study demonstrated that BG45 can upregulate the expression of synaptic proteins and reduce the loss of neurons in the hippocampus of APPswe/PS1dE9 (APP/PS1) transgenic mice (Tg). The entorhinal [...] Read more.

BG45 is a class Ⅰ histone deacetylase inhibitor (HDACI) with selectivity for HDAC3. Our previous study demonstrated that BG45 can upregulate the expression of synaptic proteins and reduce the loss of neurons in the hippocampus of APPswe/PS1dE9 (APP/PS1) transgenic mice (Tg). The entorhinal cortex is a pivotal region that, along with the hippocampus, plays a critical role in memory in the Alzheimer’s disease (AD) pathology process. In this study, we focused on the inflammatory changes in the entorhinal cortex of APP/PS1 mice and further explored the therapeutic effects of BG45 on the pathologies. The APP/PS1 mice were randomly divided into the transgenic group without BG45 (Tg group) and the BG45-treated groups. The BG45-treated groups were treated with BG45 at 2 months (2 m group), at 6 months (6 m group), or twice at 2 and 6 months (2 and 6 m group). The wild-type mice group (Wt group) served as the control. All mice were killed within 24 h after the last injection at 6 months. The results showed that amyloid-β (Aβ) deposition and IBA1-positive microglia and GFAP-positive astrocytes in the entorhinal cortex of the APP/PS1 mice progressively increased over time from 3 to 8 months of age. When the APP/PS1 mice were treated with BG45, the level of H3K9K14/H3 acetylation was improved and the expression of histonedeacetylase1, histonedeacetylase2, and histonedeacetylase3 was inhibited, especially in the 2 and 6 m group. BG45 alleviated Aβ deposition and reduced the phosphorylation level of tau protein. The number of IBA1-positive microglia and GFAP-positive astrocytes decreased with BG45 treatment, and the effect was more significant in the 2 and 6 m group. Meanwhile, the expression of synaptic proteins synaptophysin, postsynaptic density protein 95, and spinophilin was upregulated and the degeneration of neurons was alleviated. Moreover, BG45 reduced the gene expression of inflammatory cytokines interleukin-1β and tumor necrosis factor-α. Closely related to the CREB/BDNF/NF-kB pathway, the expression of p-CREB/CREB, BDNF, and TrkB was increased in all BG45 administered groups compared with the Tg group. However, the levels of p-NF-kB/NF-kB in the BG45 treatment groups were reduced. Therefore, we deduced that BG45 is a potential drug for AD by alleviating inflammation and regulating the CREB/BDNF/NF-kB pathway, and the early, repeated administration of BG45 can play a more effective role. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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16 pages, 1475 KiB

Open AccessArticle

Simultaneous Inhibition of Histone Deacetylases and RNA Synthesis Enables Totipotency Reprogramming in Pig SCNT Embryos

by Mariana Priotto de Macedo, Werner Giehl Glanzner, Karina Gutierrez, Luke Currin, Vanessa Guay, Maria Elena Carrillo Herrera, Zigomar da Silva, Hernan Baldassarre, Serge McGraw and Vilceu Bordignon

Int. J. Mol. Sci. 2022, 23(22), 14142; https://doi.org/10.3390/ijms232214142 - 16 Nov 2022

Cited by 5 | Viewed by 2607

Abstract

Combining somatic cell nuclear transfer (SCNT) with genome editing technologies has emerged as a powerful platform for the creation of unique swine lineages for agricultural and biomedical applications. However, successful application of this research platform is still hampered by the low efficiency of [...] Read more.

Combining somatic cell nuclear transfer (SCNT) with genome editing technologies has emerged as a powerful platform for the creation of unique swine lineages for agricultural and biomedical applications. However, successful application of this research platform is still hampered by the low efficiency of these technologies, particularly in attaining complete cell reprogramming for the production of cloned pigs. Treating SCNT embryos with histone deacetylase inhibitors (HDACis), such as Scriptaid, has been routinely used to facilitate chromatin reprogramming after nuclear transfer. While increasing histone acetylation leads to a more relaxed chromatin configuration that facilitates the access of reprogramming factors and DNA repair machinery, it may also promote the expression of genes that are unnecessary or detrimental for normal embryo development. In this study, we evaluated the impact of inhibiting both histone deacetylases and RNA synthesis on pre- and post-implantation development of pig SCNT embryos. Our findings revealed that transcription can be inhibited for up to 40 h of development in porcine embryos, produced either by activation, fertilization or SCNT, without detrimentally affecting their capacity to form a blastocyst and their average number of cells at this developmental stage. Importantly, inhibiting RNA synthesis during HDACi treatment resulted in SCNT blastocysts with a greater number of cells and more abundant transcripts for genes related to embryo genome activation on days 2, 3 and 4 of development, compared to SCNT embryos that were treated with HDACi only. In addition, concomitant inhibition of histone deacetylases and RNA synthesis promoted the full reprograming of somatic cells, as evidenced by the normal fetal and full-term development of SCNT embryos. This combined treatment may improve the efficiency of the genome-editing + SCNT platform in swine, which should be further tested by transferring more SCNT embryos and evaluating the health and growth performance of the cloned pigs. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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21 pages, 3887 KiB

Open AccessArticle

The Novel Class IIa Selective Histone Deacetylase Inhibitor YAK540 Is Synergistic with Bortezomib in Leukemia Cell Lines

by Lukas M. Bollmann, Alexander J. Skerhut, Yodita Asfaha, Nadine Horstick, Helmut Hanenberg, Alexandra Hamacher, Thomas Kurz and Matthias U. Kassack

Int. J. Mol. Sci. 2022, 23(21), 13398; https://doi.org/10.3390/ijms232113398 - 2 Nov 2022

Cited by 11 | Viewed by 2020

Abstract

The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance [...] Read more.

The treatment of leukemias, especially acute myeloid leukemia (AML), is still a challenge as can be seen by poor 5-year survival of AML. Therefore, new therapeutic approaches are needed to increase the treatment success. Epigenetic aberrations play a role in pathogenesis and resistance of leukemia. Histone deacetylase (HDAC) inhibitors (HDACIs) can normalize epigenetic disbalance by affecting gene expression. In order to decrease side effects of so far mainly used pan-HDACIs, this paper introduces the novel highly selective class IIa HDACI YAK540. A synergistic cytotoxic effect was observed between YAK540 and the proteasome inhibitor bortezomib (BTZ) as analyzed by the Chou-Talalay method. The combination of YAK540 and BTZ showed generally increased proapoptotic gene expression, increased p21 expression, and synergistic, caspase 3/7-mediated apoptosis. Notably, the cytotoxicity of YAK540 is much lower than that of pan-HDACIs. Further, combinations of YAK540 and BTZ are clearly less toxic in non-cancer HEK293 compared to HL-60 leukemia cells. Thus, the synergistic combination of class IIa selective HDACIs such as YAK540 and proteasome inhibitors represents a promising approach against leukemias to increase the anticancer effect and to reduce the general toxicity of HDACIs. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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16 pages, 4625 KiB

Open AccessArticle

Non-Histone Lysine Crotonylation Is Involved in the Regulation of White Fat Browning

by Yuexia Liu, Yizhou Li, Juntong Liang, Zhuwen Sun and Chao Sun

Int. J. Mol. Sci. 2022, 23(21), 12733; https://doi.org/10.3390/ijms232112733 - 22 Oct 2022

Cited by 12 | Viewed by 2289

Abstract

Lysine crotonylation modification is a novel acylation modification that is similar to acetylation modification. Studies have found that protein acetylation plays an important regulatory part in the occurrence and prevention of obesity and is involved in the regulation of glucose metabolism, tricarboxylic acid [...] Read more.

Lysine crotonylation modification is a novel acylation modification that is similar to acetylation modification. Studies have found that protein acetylation plays an important regulatory part in the occurrence and prevention of obesity and is involved in the regulation of glucose metabolism, tricarboxylic acid cycle, white fat browning and fatty acid metabolism. Therefore, we speculate that protein crotonylation may also play a more vital role in regulating the browning of white fat. To verify this conjecture, we identified 7254 crotonyl modification sites and 1629 modified proteins in iWAT of white fat browning model mice by affinity enrichment and liquid chromatography–mass spectrometry (LC-MS/MS). We selected five representative proteins in the metabolic process, namely glycerol-3-phosphate dehydrogenase 1 (GPD1), fatty acid binding protein 4 (FABP4), adenylate kinase 2 (AK2), triosephosphate isomerase 1 (TPI1) and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 8 (NDUFA8). Through qPCR, Western blotting, immunofluorescence staining, Oil Red O staining and HE staining, we demonstrated that GPD1 and FABP4 inhibited white fat browning, while AK2, TPI1 and NDUFA8 promoted white fat browning. GPD1 and FABP4 proteins were downregulated by crotonylation modification, while AK2, TPI1 and NDUFA8 proteins were upregulated by crotonylation modification. Further detection found that the crotonylation modification of GPD1, FABP4, AK2, TPI1 and NDUFA8 promoted white fat browning, which was consistent with the sequencing results. These results indicate that the protein crotonylation is involved in regulating white fat browning, which is of great significance for controlling obesity and treating obesity-related diseases. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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13 pages, 1766 KiB

Open AccessArticle

Methionine 274 Is Not the Determining Factor for Selective Inhibition of Histone Deacetylase 8 (HDAC8) by L-Shaped Inhibitors

by Niklas Jänsch, Kim Leoni Lang and Franz-Josef Meyer-Almes

Int. J. Mol. Sci. 2022, 23(19), 11775; https://doi.org/10.3390/ijms231911775 - 4 Oct 2022

Cited by 6 | Viewed by 2536

Abstract

HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a “switch” that controls a transient binding [...] Read more.

HDAC8 is an important target in several indication areas including childhood neuroblastoma. Several isozyme selective inhibitors of HDAC8 with L-shaped structures have been developed. A theoretical study has suggested that methionine 274 (M274) would act as a “switch” that controls a transient binding pocket, which is induced upon binding of L-shaped inhibitors. This hypothesis was experimentally examined in this study. The thermostability and functionality of HDAC8 wildtype and mutant variants with exchanged M274 were analyzed using biophysical methods. Furthermore, the binding kinetics of L-shaped and linear reference inhibitors of these HDAC8 variants were determined in order to elucidate the mode of interaction. Exchange of M274 has considerable impact on enzyme activity, but is not the decisive factor for selective recognition of HDAC8 by L-shaped inhibitors. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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27 pages, 18173 KiB

Open AccessArticle

Chidamide plus Tyrosine Kinase Inhibitor Remodel the Tumor Immune Microenvironment and Reduce Tumor Progression When Combined with Immune Checkpoint Inhibitor in Naïve and Anti-PD-1 Resistant CT26-Bearing Mice

by Jia-Shiong Chen, Yi-Chien Hsieh, Cheng-Han Chou, Yi-Hong Wu, Mu-Hsuan Yang, Sz-Hao Chu, Ye-Su Chao and Chia-Nan Chen

Int. J. Mol. Sci. 2022, 23(18), 10677; https://doi.org/10.3390/ijms231810677 - 14 Sep 2022

Cited by 8 | Viewed by 3601

Abstract

Combined inhibition of vascular endothelial growth factor receptor (VEGFR) and the programmed cell death protein 1 (PD-1) pathways has shown efficacy in multiple cancers; however, the clinical outcomes show limited benefits and the unmet clinical needs still remain and require improvement in efficacy. [...] Read more.

Combined inhibition of vascular endothelial growth factor receptor (VEGFR) and the programmed cell death protein 1 (PD-1) pathways has shown efficacy in multiple cancers; however, the clinical outcomes show limited benefits and the unmet clinical needs still remain and require improvement in efficacy. Using murine colon carcinoma (CT26) allograft models, we examined the efficacy and elucidated novel tumor microenvironment (TME) remodeling mechanisms underlying the combination of chidamide (a benzamide-based class l histone deacetylase inhibitor; brand name in Taiwan, Kepida^®) with VEGF receptor tyrosine kinase inhibitor (TKIs; cabozantinib/regorafenib, etc.) and immune checkpoint inhibitors (ICIs; anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies). The TME was assessed using flow cytometry and RNA-sequencing to determine the novel mechanisms and their correlation with therapeutic effects in mice with significant treatment response. Compared with ICI alone or cabozantinib/regorafenib + ICI, combination of chidamide + cabozantinib/regorafenib + ICI increased the tumor response and survival benefits. In particular, treatment of CT26-bearing mice with chidamide + regorafenib + anti-PD-1 antibody showed a better objective response rate (ORR) and overall survival (OS). Similar results were observed in anti-PD-1 treatment-resistant mice. After treatment with this optimal combination, in the TME, RNA-sequencing revealed that downregulated mRNAs were correlated with leukocyte migration, cell chemotaxis, and macrophage gene sets, and flow cytometry analysis showed that the cell numbers of myeloid-derived polymorphonuclear suppressor cells and tumor-associated macrophages were decreased. Accordingly, chidamide + regorafenib + anti-PD-1 antibody combination therapy could trigger a novel TME remodeling mechanism by attenuating immunosuppressive cells, and restoring T-cell activation to enhance ORR and OS. Our studies also showed that the addition of Chidamide to the regorafenib + anti-PD-1 Ab combination could induce a durable tumor-specific response by attenuating immune suppression in the TME. In addition, this result suggests that TME remodeling, mediated by epigenetic immunomodulator combined with TKI and ICI, would be more advantageous for achieving a high objective response rate, when compared to TKI plus ICI or ICI alone, and maintaining long-lasting antitumor activity. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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18 pages, 2373 KiB

Open AccessArticle

Acetylation-Specific Interference by Anti-Histone H3K9ac Intrabody Results in Precise Modulation of Gene Expression

by Simonetta Lisi, Matteo Trovato, Ottavia Vitaloni, Marco Fantini, Michele Chirichella, Paola Tognini, Sara Cornuti, Mario Costa, Marco Groth and Antonino Cattaneo

Int. J. Mol. Sci. 2022, 23(16), 8892; https://doi.org/10.3390/ijms23168892 - 10 Aug 2022

Cited by 2 | Viewed by 2793

Abstract

Among Histone post-translational modifications (PTMs), lysine acetylation plays a pivotal role in the epigenetic regulation of gene expression, mediated by chromatin modifying enzymes. Due to their activity in physiology and pathology, several chemical compounds have been developed to inhibit the function of these [...] Read more.

Among Histone post-translational modifications (PTMs), lysine acetylation plays a pivotal role in the epigenetic regulation of gene expression, mediated by chromatin modifying enzymes. Due to their activity in physiology and pathology, several chemical compounds have been developed to inhibit the function of these proteins. However, the pleiotropy of these classes of proteins represents a weakness of epigenetic drugs. Ideally, a new generation of epigenetic drugs should target with molecular precision individual acetylated lysines on the target protein. We exploit a PTM-directed interference, based on an intrabody (scFv-58F) that selectively binds acetylated lysine 9 of histone H3 (H3K9ac), to test the hypothesis that targeting H3K9ac yields more specific effects than inhibiting the corresponding HAT enzyme that installs that PTM. In yeast scFv-58F modulates, gene expression in a more specific way, compared to two well-established HAT inhibitors. This PTM-specific interference modulated expression of genes involved in ribosome biogenesis and function. In mammalian cells, the scFv-58F induces exclusive changes in the H3K9ac-dependent expression of specific genes. These results suggest the H3K9ac-specific intrabody as the founder of a new class of molecules to directly target histone PTMs, inverting the paradigm from inhibiting the writer enzyme to acting on the PTM. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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23 pages, 5802 KiB

Open AccessArticle

Analysis of Givinostat/ITF2357 Treatment in a Rat Model of Neonatal Hypoxic-Ischemic Brain Damage

by Paulina Pawelec, Joanna Sypecka, Teresa Zalewska and Malgorzata Ziemka-Nalecz

Int. J. Mol. Sci. 2022, 23(15), 8287; https://doi.org/10.3390/ijms23158287 - 27 Jul 2022

Cited by 2 | Viewed by 2438

Abstract

The histone deacetylase inhibitor (HDACi) Givinostat/ITF2357 provides neuroprotection in adult models of brain injury; however, its action after neonatal hypoxia-ischemia (HI) is still undefined. The aim of our study was to test the hypothesis that the mechanism of Givinostat is associated with the [...] Read more.

The histone deacetylase inhibitor (HDACi) Givinostat/ITF2357 provides neuroprotection in adult models of brain injury; however, its action after neonatal hypoxia-ischemia (HI) is still undefined. The aim of our study was to test the hypothesis that the mechanism of Givinostat is associated with the alleviation of inflammation. For this purpose, we analyzed the microglial response and the effect on molecular mediators (chemokines/cytokines) that are crucial for inducing cerebral damage after neonatal hypoxia-ischemia. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 60 min of hypoxia (7.6% O₂). Givinostat (10 mg/kg b/w) was administered in a 5-day regimen. The effects of Givinostat on HI-induced inflammation (cytokine, chemokine and microglial activation and polarization) were assessed with a Luminex assay, immunohistochemistry and Western blot. Givinostat treatment did not modulate the microglial response specific for HI injury. After Givinostat administration, the investigated chemokines and cytokines remained at the level induced by HI. The only immunosuppressive effect of Givinostat may be associated with the decrease in MIP-1α. Neonatal hypoxia-ischemia produces an inflammatory response by activating the proinflammatory M1 phenotype of microglia, disrupting the microglia–neuron (CX3CL1/CX3CR1) axis and elevating numerous proinflammatory cytokines/chemokines. Givinostat/ITF2357 did not prevent an inflammatory reaction after HI. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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13 pages, 2218 KiB

Open AccessArticle

Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci

by Alvin Susetyo, Sumiyasu Ishii, Yuki Fujiwara, Izuki Amano and Noriyuki Koibuchi

Int. J. Mol. Sci. 2022, 23(14), 7869; https://doi.org/10.3390/ijms23147869 - 17 Jul 2022

Cited by 7 | Viewed by 1899

Abstract

Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. The thyroid hormone receptor binds to corepressor complexes containing histone deacetylase (HDAC) 3 in the absence of ligands and acts as a transcriptional repressor. Although histone acetylation status is strongly correlated with [...] Read more.

Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. The thyroid hormone receptor binds to corepressor complexes containing histone deacetylase (HDAC) 3 in the absence of ligands and acts as a transcriptional repressor. Although histone acetylation status is strongly correlated with transcriptional regulation, its role in cerebellar development remains largely unknown. We aimed to study whether the cerebellar developmental defects induced by perinatal hypothyroidism can be rescued by treatment with a specific HDAC3 inhibitor, RGFP966. Motor coordination was analyzed using three behavioral tests. The cerebella were subjected to RT-qPCR and chromatin immunoprecipitation assays for acetylated histone H3. The treatment with RGFP966 partially reversed the cerebellar morphological defects in perinatal hypothyroid mice. These findings were associated with the alleviation of motor coordination defects in these mice. In addition, the RGFP966 administration increased the mRNA levels of cerebellar thyroid hormone-responsive genes. These increases were accompanied by augmented histone acetylation status at these gene loci. These findings indicate that HDAC3 plays an important role in the cerebellar developmental defects induced by perinatal hypothyroidism. The HDAC3 inhibitor might serve as a novel therapeutic agent for hypothyroidism-induced cerebellar defects by acetylating histone tails and stimulating transcription at thyroid hormone-responsive gene loci. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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31 pages, 13035 KiB

Open AccessArticle

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

by Salma Darwish, Ehab Ghazy, Tino Heimburg, Daniel Herp, Patrik Zeyen, Rabia Salem-Altintas, Johannes Ridinger, Dina Robaa, Karin Schmidtkunz, Frank Erdmann, Matthias Schmidt, Christophe Romier, Manfred Jung, Ina Oehme and Wolfgang Sippl

Int. J. Mol. Sci. 2022, 23(14), 7535; https://doi.org/10.3390/ijms23147535 - 7 Jul 2022

Cited by 23 | Viewed by 3325

Abstract

In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell [...] Read more.

In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell lines. As shown in several studies, HDAC8 can be considered a potential target in the treatment of cancer forms such as childhood neuroblastoma. The present work describes the development of proteolysis targeting chimeras (PROTACs) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we investigated the HDAC8-degrading profiles of the synthesized PROTACs and their effect on the proliferation of neuroblastoma cells. The combination of in vitro screening and cellular testing demonstrated selective HDAC8 PROTACs that show anti-neuroblastoma activity in cells. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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14 pages, 4210 KiB

Open AccessArticle

Improvement of Cognitive Function in Ovariectomized Rats by Human Neural Stem Cells Overexpressing Choline Acetyltransferase via Secretion of NGF and BDNF

by Eun-Jung Yoon, Yunseo Choi and Dongsun Park

Int. J. Mol. Sci. 2022, 23(10), 5560; https://doi.org/10.3390/ijms23105560 - 16 May 2022

Cited by 11 | Viewed by 2532

Abstract

Menopause is associated with memory deficits attributed to reduced serum estrogen levels. We evaluated whether an increase in brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF) levels, through transplantation of choline acetyltransferase (ChAT)-overexpressing neural stem cells (F3.ChAT), improved learning and memory in ovariectomized [...] Read more.

Menopause is associated with memory deficits attributed to reduced serum estrogen levels. We evaluated whether an increase in brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF) levels, through transplantation of choline acetyltransferase (ChAT)-overexpressing neural stem cells (F3.ChAT), improved learning and memory in ovariectomized rats. PD13 mouse neuronal primary culture cells were treated with estradiol or co-cultured with F3.ChAT cells; choline transporter1 (CHT1), ChAT, and vesicular acetylcholine transporter (VAChT) expression was evaluated using real-time PCR. The relationship between estrogen receptors (ERs) and neurotrophin family members was analyzed using immunohistochemistry. After the transplantation of F3.ChAT cells into OVx rats, we evaluated the memory, ACh level, and the expression of ER, neurotrophin family proteins, and cholinergic system. Estradiol upregulated CHT1, ChAT, and VAChT expression in ER; they were co-localized with BDNF, NGF, and TrkB. Co-culture with F3.ChAT upregulated CHT1, ChAT, and VAChT by activating the neurotrophin signalling pathway. Transplantation of F3.ChAT cells in OVX animals increased the ACh level in the CSF and improved memory deficit. In addition, it increased the expression of ERs, neurotrophin signaling, and the cholinergic system in the brains of OVX animals. Therefore, the estradiol deficiency induced memory loss by the down-regulation of the neurotrophin family and F3.ChAT could ameliorate the cognitive impairment owing to the loss or reduction of estradiol. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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Review

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23 pages, 1456 KiB

Open AccessReview

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs

by Karla Rubio, Alejandro Molina-Herrera, Andrea Pérez-González, Hury Viridiana Hernández-Galdámez, Carolina Piña-Vázquez, Tania Araujo-Ramos and Indrabahadur Singh

Int. J. Mol. Sci. 2023, 24(15), 12302; https://doi.org/10.3390/ijms241512302 - 1 Aug 2023

Cited by 9 | Viewed by 2615

Abstract

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, [...] Read more.

Fibrosis is a condition characterized by the excessive accumulation of extracellular matrix proteins in tissues, leading to organ dysfunction and failure. Recent studies have identified EP300, a histone acetyltransferase, as a crucial regulator of the epigenetic changes that contribute to fibrosis. In fact, EP300-mediated acetylation of histones alters global chromatin structure and gene expression, promoting the development and progression of fibrosis. Here, we review the role of EP300-mediated epigenetic regulation in multi-organ fibrosis and its potential as a therapeutic target. We discuss the preclinical evidence that suggests that EP300 inhibition can attenuate fibrosis-related molecular processes, including extracellular matrix deposition, inflammation, and epithelial-to-mesenchymal transition. We also highlight the contributions of small molecule inhibitors and gene therapy approaches targeting EP300 as novel therapies against fibrosis. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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Open AccessReview

Role of Histone Deacetylases in T-Cell Development and Function

by Monika Pieniawska and Katarzyna Iżykowska

Int. J. Mol. Sci. 2022, 23(14), 7828; https://doi.org/10.3390/ijms23147828 - 15 Jul 2022

Cited by 3 | Viewed by 2463

Abstract

Histone deacetylases (HDACs) are a group of enzymes called “epigenetic erasers”. They remove the acetyl group from histones changing the condensation state of chromatin, leading to epigenetic modification of gene expression and various downstream effects. Eighteen HDACs have been identified and grouped into [...] Read more.

Histone deacetylases (HDACs) are a group of enzymes called “epigenetic erasers”. They remove the acetyl group from histones changing the condensation state of chromatin, leading to epigenetic modification of gene expression and various downstream effects. Eighteen HDACs have been identified and grouped into four classes. The role of HDACs in T-cells has been extensively studied, and it has been proven that many of them are important players in T-cell development and function. In this review, we present the current state of knowledge on the role of HDACs in the early stages of T-cell development but also in the functioning of mature lymphocytes on the periphery, including activation, cytokine production, and metabolism regulation. Full article

(This article belongs to the Special Issue Histone Acetyltransferase and Deacetylase Inhibitors - New Aspects and Developments)

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