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Background: Acne vulgaris (AV) is a highly prevalent skin inflammatory disorder. Histone modifications are common epigenetic processes, which happen secondary to environmental conditions. One of the many biological pathways' epigenetic regulation mechanisms is histone acetylation and deacetylation. Objective: To evaluate the serum levels of histone deacetylase 1 (HDAC1) enzyme in AV cases and to examine their correlation with AV severity. Patients and Methods: A case-control study was conducted on 90 participants: 45 patients with acne vulgaris and 45 healthy controls (HC). Global acne grading system (GAGS) was calculated. Then, serum HDAC1 level was measured by using ELISA. Results: Cases showed significantly higher HDAC1 level when compared to control group. HDAC1 among case group showed a significant gradual increase in mild, moderate, severe, and very severe grades. Moreover, positive significant correlation with the score of acne vulgaris was demonstrated (p<0.001). Conclusion: Human histone deacetylases1 (HDAC1) appears to be dysregulated in cases with AV. This could suggest a possible therapeutic opportunity for HDAC inhibitors for AV management. [ABSTRACT FROM AUTHOR]

Histone acetylation is a pivotal epigenetic modification that controls chromatin structure and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confine the utilization of the zygotic genome remain to be elucidated. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from mid-blastula and onward. The recruitment of Hdac1 to the genome at blastula is instructed maternally. Cis-regulatory modules (CRMs) bound by Hdac1 possess epigenetic signatures underlying distinct functions. We highlight a dual function model of Hdac1 where Hdac1 not only represses gene expression by sustaining a histone hypoacetylation state on inactive chromatin, but also maintains gene expression through participating in dynamic histone acetylation-deacetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities, both in time and space. Taken together, our study reveals a comprehensive role for Hdac1 during early vertebrate embryogenesis.

Hepatic ischemia‐reperfusion (IR) injury is a complex systemic process causing a series clinical problem. C/EBPα is a key transcription factor for hepatocyte function, but its role and mechanism in regulating hepatic IR injury are largely unknown. Occluding portal vein and hepatic artery was used to establish a mouse model of hepatic IR injury. C/EBPα expression was decreased in IR‐injured liver compared with the sham, accompanied by increased contents of serum alanine transaminase (ALT), aspartate transaminase (AST), high mobility group box‐1, and proportion of hepatic cells. Oxygen and glucose deprivation/recovery (OGD/R) was used to establish a cellular hepatic IR model in WRL‐68 hepatocytes in vitro, and C/EBPα was overexpressed in the hepatocytes to evaluate its effect on hepatic IR injury. OGD/R promoted oxidative stress, cell apoptosis and endoplasmic reticulum (ER) stress in hepatocytes, which was reversed by C/EBPα overexpression. Then, we found that C/EBPα promoted histone deacetylase 1 (HDAC1) transcription through binding to HDAC1 promoter. Moreover, HDAC1 deacetylated the activating transcription factor 4 (ATF4), a key positive regulator of ER stress. Trichostatin‐A (an HDAC inhibitor) or ATF4 overexpression reversed the improvement of C/EBPα on OGD/R‐induced ER stress and hepatocyte dysfunction. 4‐Phenylbutyric acid (an endoplasmic reticulum stress inhibitor) also reversed the hepatic IR injury induced by ATF4 overexpression. Finally, lentivirus‐mediated C/EBPα overexpression vector was applied to administrate hepatic IR mice, and the results showed that C/EBPα overexpression ameliorated IR‐induced hepatic injury, manifesting with reduced ALT/AST, oxidative stress and ER stress. Altogether, our findings suggested that C/EBPα ameliorated hepatic IR injury by inhibiting ER stress via HDAC1‐mediated deacetylation of ATF4 promoter. [ABSTRACT FROM AUTHOR]

Classical swine fever virus (CSFV) poses a major threat to the pig industry. The mechanisms that CSFV uses to evade host innate immunity are not fully understood. Acetylation of histones and non-histone proteins is involved in modulating innate immune responses. Histone deacetylase 1 (HDAC1) could be proviral or antiviral by modulating the acetylation status of histones, viral proteins or non-histone host proteins, depending on the type of viruses involved. First, we found that CSFV infection in IPEC-J2 cells resulted in reduced expression of HDAC1. By chemical inhibition, gene silencing, and overexpression, we revealed that HDAC1 acts as a negative regulator of CSFV replication in IPEC-J2 cells probably through activation of poly(I:C) and IFN-λ3-induced IFN-I/III innate immunity. Mechanistically, CSFV Npro downregulated HDAC1 and its transcriptional regulator specificity protein 1 (Sp1). Npro interacted with Sp1 to facilitate its degradation through the ubiquitin-proteasome pathway via its N-terminal domain, a region that does not have significant effect on IRF3 stability. Thus, it is clear that CSFV deploys the two domains of its Npro to counteract the innate immune responses, the C-terminal one targeting the IRF3 pathway as previously reported, and the N-terminal one targeting the Sp1-HDAC1 axis. IMPORTANCE Of the flaviviruses, only CSFV and bovine viral diarrhea virus express Npro as the non-structural protein which is not essential for viral replication but functions to dampen host innate immunity. We have deciphered a novel mechanism with which CSFV uses to evade the host antiviral immunity by the N-terminal domain of its Npro to facilitate proteasomal degradation of Sp1 with subsequent reduction of HDAC1 and ISG15 expression. This is distinct from earlier findings involving Npro-mediated IRF3 degradation via the C-terminal domain. This study provides insights for further studies on how HDAC1 plays its role in antiviral immunity, and if and how other viral proteins, such as the core protein of CSFV, the nucleocapsid protein of porcine epidemic diarrhea virus, or even other coronaviruses, exert antiviral immune responses via the Sp1-HDAC1 axis. Such research may lead to a deeper understanding of viral immune evasion strategies as part of their pathogenetic mechanisms. [ABSTRACT FROM AUTHOR]

Increased expression of vascular cell adhesion molecule (VCAM)-1 on the activated arterial endothelial cell (EC) surface critically contributes to atherosclerosis which may in part be regulated by epigenetic mechanisms. This study investigated whether and how the clinically available histone deacetylases 1 and 2 (HDAC1/2) inhibitor drug Romidepsin epigenetically modulates VCAM-1 expression to suppress atherosclerosis. Methods: VCAM-1 expression was analyzed in primary human aortic EC (HAEC) treated with Romidepsin or transfected with HDAC1/2-targeting siRNA. Methylation of GATA6 promoter region was examined with methylation-specific PCR assay. Enrichment of STAT3 to GATA6 promoter was detected with chromatin immunoprecipitation. Lys685Arg mutation was constructed to block STAT3 acetylation. The potential therapeutic effect of Romidepsin on atherosclerosis was evaluated in Apoe -/- mice fed with a high-fat diet. Results: Romidepsin significantly attenuated TNFα-induced VCAM-1 expression on HAEC surface and monocyte adhesion through simultaneous inhibition of HDAC1/2. This downregulation of VCAM-1 was attributable to reduced expression of transcription factor GATA6. Romidepsin enhanced STAT3 acetylation and its binding to DNA methyltransferase 1 (DNMT1), leading to hypermethylation of the GATA6 promoter CpG-rich region at +140/+255. Blocking STAT3 acetylation at Lys685 disrupted DNMT1-STAT3 interaction, decreased GATA6 promoter methylation, and reversed the suppressive effects of HDAC1/2 inhibition on GATA6 and VCAM-1 expression. Finally, intraperitoneal administration of Romidepsin reduced diet-induced atherosclerotic lesion development in Apoe -/- mice, accompanied by a reduction in GATA6/VCAM-1 expression in the aorta. Conclusions: HDAC1/2 contributes to VCAM-1 expression and atherosclerosis by suppressing STAT3 acetylation-dependent GATA6 promoter methylation. These findings may provide a rationale for HDAC1/2-targeting therapy in atherosclerotic heart disease.

During spermatogenesis, meiosis is accompanied by a robust alteration in gene expression and chromatin status. However, it remains elusive how the meiotic transcriptional program is established to ensure completion of meiotic prophase. Here, we identify a protein complex that consists of germ-cell-specific zinc-finger protein ZFP541 and its interactor KCTD19 as the key transcriptional regulators in mouse meiotic prophase progression. Our genetic study shows that ZFP541 and KCTD19 are co-expressed from pachytene onward and play an essential role in the completion of the meiotic prophase program in the testis. Furthermore, our ChIP-seq and transcriptome analyses identify that ZFP541 binds to and suppresses a broad range of genes whose function is associated with biological processes of transcriptional regulation and covalent chromatin modification. The present study demonstrates that a germ-cell specific complex that contains ZFP541 and KCTD19 promotes the progression of meiotic prophase towards completion in male mice, and triggers the reconstruction of the transcriptional network and chromatin organization leading to post-meiotic development.

Marek's disease virus (MDV) encodes a basic-leucine zipper (BZIP) protein, Meq, which is considered the major MDV oncoprotein. It has been reported that the oncogenicity of Meq is associated with its interaction with C-terminal binding protein 1 (CtBP), which is also an interaction partner of Epstein-Barr virus encoded EBNA3A and EBNA3C oncoproteins. Since both EBNA3C and CtBP interact with histone deacetylase 1 (HDAC1) and HDAC2, we examined whether Meq shares this interaction with chicken HDAC1 (chHDAC1) and chHDAC2. Using confocal microscopy analysis, we show that Meq co-localizes with chHDAC1 and chHDAC2 in the nuclei of MDV lymphoblastoid tumor cells. In addition, immunoprecipitation assays demonstrate that Meq interacts with chHDAC1 and chHDAC2 in transfected cells and MDV lymphoblastoid tumor cells. Using deletion mutants, interaction domains were mapped to the N-terminal dimerization domain of chHDAC1 and chHDAC2, and the BZIP domain of Meq. Our results further demonstrate that this interaction mediates the degradation of chHDAC1 and chHDAC2 via the proteasome dependent pathway. In addition, our results show that Meq also induces the reduction of global ubiquitinated proteins through a proteasome dependent pathway. In conclusion, our results provide evidence that Meq interacts with chHDAC1 and chHDAC2, and induces their proteasome dependent degradation.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system abnormally reacts against cells and tissues leading to inflammation. Epigenetic alterations, including DNA methylation and histone modification, have critical effects on autoimmune disease and SLE pathogenesis via dysregulation of critical genes. The purpose of this study was to evaluate the epigenetic-related gene expression of DNA methyltransferase (DNMT) and histone deacetylase 1 (HDAC1) in Iranian patients with SLE. This matched case–control study included 16 people with SLE and 16 healthy people who were referred to the Rafsanjani rheumatology clinic, in southeast Iran. The expression of DNMT and HDAC1 genes was measured through a real-time PCR assay of blood samples. DNMT gene expression did not differ significantly between SLE and healthy groups (P = 0.21). In contrast, HDAC1 gene expression was enhanced in the SLE group, but this enhancement failed to reach statistical significance (P = 0.94). The results of this study suggest that overexpression of HDAC1 could serve as a diagnostic for SLE disease. Additional studies with larger sample sizes are required to confirm our findings. Evaluation of other genes related to SLE disease is essential and may help to make an accurate diagnosis of the disease. [ABSTRACT FROM AUTHOR]

Cancer is one of the important factors threatening human health. Hence, it is essential to create novel potent drugs to treat it. Due to the strong correlation among histone deacetylase1 (HDAC1), speckle-type POZ protein (SPOP) and cancers, dual inhibition of HDAC1 and SPOP may be a promising strategy for cancer treatment. In this study, we successfully identified four potential dualtargeting HDAC1/SPOP candidate compounds with structure-based virtual screening. In vitro inhibition experiments confirmed that the four compounds had dual inhibitory effects on HDAC1 and SPOP. Among them, compound HS-2 had a stronger inhibitory effect on HDAC1 and SPOP than the positive controls. Further molecular dynamics simulations indicated that HS-2 could stably bind to HDAC1 and SPOP. In addition, MTT assay indicated that HS-2 inhibited the growth of tumor cells in the micromolar range. In vivo evaluation showed that HS-2 could obviously inhibit the growth of tumor in nude mice without obvious toxicity. These findings suggest that HS-2 is a novel and potent dual-targeting HDAC1/SPOP inhibitor for cancer treatment. [ABSTRACT FROM AUTHOR]

Transcription growth factor β (TGF-β) signaling-triggered epithelial-to-mesenchymal transition (EMT) process is associated with tumor stemness, metastasis, and chemotherapy resistance. However, the epigenomic basis for TGF-β-induced EMT remains largely unknown. Here we reveal that HDAC1-mediated global histone deacetylation and the gain of specific histone H3 lysine 27 acetylation (H3K27ac)-marked enhancers are essential for the TGF-β-induced EMT process. Enhancers gained upon TGF-β treatment are linked to gene activation of EMT markers and cancer metastasis. Notably, dynamic enhancer gain or loss mainly occurs within pre-existing topologically associated domains (TADs) in epithelial cells, with minimal three-dimensional (3D) genome architecture reorganization. Through motif enrichment analysis of enhancers that are lost or gained upon TGF-β stimulation, we identify FOXA2 as a key factor to activate epithelial-specific enhancer activity, and we also find that TEAD4 forms a complex with SMAD2/3 to mediate TGF-β signaling-triggered mesenchymal enhancer reprogramming. Together, our results implicate that key transcription-factor (TF)-mediated enhancer reprogramming modulates the developmental transition in TGF-β signaling-associated cancer metastasis.

Isoprenoid pyrophosphates are involved in protein prenylation and assume regulatory roles in cells; however, little is known about the cellular proteins that can interact with isoprenoid pyrophosphates. Here, we devised a chemical proteomic strategy, capitalizing on the use of a desthiobiotin-geranyl pyrophosphate (GPP) acyl phosphate probe for the enrichment and subsequent identification of GPP-binding proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). By combining stable isotope labeling by amino acids in cell culture (SILAC) and competitive labeling with low vs high concentrations of GPP probe, with ATP vs GPP acyl phosphate probes, or with the GPP probe in the presence of different concentrations of free GPP, we uncovered a number of candidate GPP-binding proteins. We also discovered, for the first time, histone deacetylase 1 (HDAC1) as a GPP-binding protein. Furthermore, we found that the enzymatic activity of HDAC1 could be modulated by isoprenoid pyrophosphates. Together, we developed a novel chemical proteomic method for the proteome-wide discovery of GPP-binding proteins, which sets the stage for a better understanding about the biological functions of isoprenoids.

TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD-TDP underlying TDP-43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD-TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD-TDP. TDP-43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD-TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP-43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD-TDP.

High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2 inhibitor romidepsin (FK228) and siRNAs, we determined roles of HDAC1 and HDAC2 in HFD-induced hypertension and found the pathologic signaling axis between HDAC1 and Agt transcription. Treatment with FK228 canceled the increased blood pressure of male C57BL/6 mice induced by HFD. FK228 also blocked upregulation of renal Agt mRNA, protein, angiotensin II (Ang II) or serum Ang II. Activation and nuclear accumulation of both HDAC1 and HDAC2 occurred in the HFD group. The HFD-induced HDAC activation was associated with an increase in deacetylated c-Myc transcription factor. Silencing of HDAC1, HDAC2 or c-Myc in HRPTEpi cells decreased Agt expression. However, only HDAC1 knockdown, but not HDAC2, increased c-Myc acetylation, suggesting selective roles in two enzymes. Chromatin immunoprecipitation assay revealed that HFD induced the binding of HDAC1 and deacetylated c-Myc at the Agt gene promoter. A putative c-Myc binding sequence in the promotor region was necessary for Agt transcription. Inhibition of c-Myc downregulated Agt and Ang II levels in kidney and serum, ameliorating HFD-induced hypertension. Thus, the abnormal HDAC1/2 in the kidney may be responsible for the upregulation of the Agt gene expression and hypertension. The results expose the pathologic HDAC1/c-myc signaling axis in kidney as a promising therapeutic target for obesity-associated resistant hypertension.

ABSTRACT Porcine epidemic diarrhea virus (PEDV) is the main etiologic agent causing acute swine epidemic diarrhea, leading to severe economic losses to the pig industry. PEDV has evolved to deploy complicated antagonistic strategies to escape from host antiviral innate immunity. Our previous study demonstrated that PEDV downregulates histone deacetylase 1 (HDAC1) expression by binding viral nucleocapsid (N) protein to the transcription factor Sp1, inducing enhanced protein acetylation. We hypothesized that PEDV inhibition of HDAC1 expression would enhance acetylation of the molecules critical in innate immune signaling. Signal transducer and activator of transcription 1 (STAT1) is a crucial transcription factor regulating expression of interferon (IFN)-stimulated genes (ISGs) and anti-PEDV immune responses, as shown by overexpression, chemical inhibition, and gene knockdown in IPEC-J2 cells. We further show that PEDV infection and its N protein overexpression, although they upregulated STAT1 transcription level, could significantly block poly(I·C) and IFN-λ3-induced STAT1 phosphorylation and nuclear localization. Western blotting revealed that PEDV and its N protein promote STAT1 acetylation via downregulation of HDAC1. Enhanced STAT1 acetylation due to HDAC1 inhibition by PEDV or MS-275 (an HDAC1 inhibitor) impaired STAT1 phosphorylation, indicating that STAT1 acetylation negatively regulated its activation. These results, together with our recent report on PEDV N-mediated inhibition of Sp1, clearly indicate that PEDV manipulates the Sp1-HDAC1-STAT1 signaling axis to inhibit transcription of OAS1 and ISG15 in favor of its replication. This novel immune evasion mechanism is realized by suppression of STAT1 activation through preferential modulation of STAT1 acetylation over phosphorylation as a result of HDAC1 expression inhibition. IMPORTANCE PEDV has developed sophisticated evasion mechanisms to escape host IFN signaling via its structural and nonstructural proteins. STAT1 is one of the key transcription factors in regulating expression of ISGs. We found that PEDV and its N protein inhibit STAT1 phosphorylation and nuclear localization via inducing STAT1 acetylation as a result of HDAC1 downregulation, which, in turn, dampens the host IFN signaling activation. Our study demonstrates a novel mechanism that PEDV evades host antiviral innate immunity through manipulating the reciprocal relationship of STAT1 acetylation and phosphorylation. This provides new insights into the pathogenetic mechanisms of PEDV and even other coronaviruses.

Long noncoding RNAs (lncRNAs) can regulate target gene expression by acting in cis (locally) or in trans (non-locally). Here, we performed genome-wide expression analysis of Toll-like receptor (TLR)-stimulated human macrophages to identify pairs of cis-acting lncRNAs and protein-coding genes involved in innate immunity. A total of 229 gene pairs were identified, many of which were commonly regulated by signaling through multiple TLRs and were involved in the cytokine responses to infection by group B Streptococcus We focused on elucidating the function of one lncRNA, named lnc-MARCKS or ROCKI (Regulator of Cytokines and Inflammation), which was induced by multiple TLR stimuli and acted as a master regulator of inflammatory responses. ROCKI interacted with APEX1 (apurinic/apyrimidinic endodeoxyribonuclease 1) to form a ribonucleoprotein complex at the MARCKS promoter. In turn, ROCKI-APEX1 recruited the histone deacetylase HDAC1, which removed the H3K27ac modification from the promoter, thus reducing MARCKS transcription and subsequent Ca2+ signaling and inflammatory gene expression. Finally, genetic variants affecting ROCKI expression were linked to a reduced risk of certain inflammatory and infectious disease in humans, including inflammatory bowel disease and tuberculosis. Collectively, these data highlight the importance of cis-acting lncRNAs in TLR signaling, innate immunity, and pathophysiological inflammation.

This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor β (RARβ) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARβ and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARβ and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARβ and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARβ were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARβ via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.

Nerve injury can induce aberrant changes in ion channels, enzymes, and cytokines/chemokines in the dorsal root ganglia (DRGs); these changes are due to or at least partly governed by transcription factors that contribute to the genesis of neuropathic pain. However, the involvement of transcription factors in neuropathic pain is poorly understood. In this study, we report that transcription factor (TF) ETS proto-oncogene 1 (ETS1) is required for the initiation and development of neuropathic pain. Sciatic nerve chronic constrictive injury (CCI, a clinical neuropathic pain model) increases ETS1 expression in the injured male mouse DRG. Blocking this upregulation alleviated CCI-induced mechanical allodynia and thermal hyperalgesia, with no apparent effect on locomotor function. Mimicking this upregulation results in the genesis of nociception hypersensitivity; mechanistically, nerve injury-induced ETS1 upregulation promotes the expression of histone deacetylase 1 (HDAC1, a key initiator of pain) via enhancing its binding activity to the HDAC1 promotor, leading to the elevation of spinal central sensitization, as evidenced by increased expression of p-ERK1/2 and GFAP in the dorsal spinal horn. It appears that the ETS1/HDAC1 axis in DRG may have a critical role in the development and maintenance of neuropathic pain, and ETS1 is a potential therapeutic target in neuropathic pain. [ABSTRACT FROM AUTHOR]

To investigate the effect and mechanism of trichostatin A on bleomycin induced pulmonary fibrosis in mice compared with dexamethasone and pirfenidone is the objective of the study. C57 black 6 mice were instilled intranasal bleomycin to establish pulmonary fibrosis model. They were divided into five groups: Control group, model group, dexamethasone group, pirfenidone group and trichostatin A group. Hematoxylin and eosin staining and Masson's staining was conducted; the expression of related proteins in each group was observed by immunohistochemistry and Western blotting. Hematoxylin and eosin staining and Masson's staining showed that the lung tissue was damaged in varying degrees, interstitial protein deposition, basal cell hyperplasia and a large number of macrophage infiltration in the alveolar cavity. The lung tissue injury in trichostatin A group was the least. The expression of vimentin, collagen-I, alpha smooth muscle actin and other interstitial proteins in the model group increased significantly, and the expression of above interstitial proteins in each intervention treatment group decreased in varying degrees, especially in trichostatin A group. The expression of suppressor of mothers against decapentaplegic homolog 7 protein decreased significantly in the model group and increased significantly in the trichostatin A group; there was no significant difference in the expression of p38-mitogen-activated protein kinase protein in each group. The expression of interstitial protein messenger RNA such as vimentin, collagen-I and alpha smooth muscle actin peaked on the 14th d after modeling. Trichostatin A could significantly inhibit the progression of pulmonary fibrosis by inhibiting the activity of histone deacetylase 1, while histone deacetylase 1 could activate transforming growth factor beta-1/suppressor of mothers against decapentaplegic pathway, involved in the progression of pulmonary fibrosis. Dexamethasone could not delay or improve pulmonary fibrosis, or even aggravate the progression of pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Nerve injury can induce aberrant changes in ion channels, enzymes, and cytokines/chemokines in the dorsal root ganglia (DRGs); these changes are due to or at least partly governed by transcription factors that contribute to the genesis of neuropathic pain. However, the involvement of transcription factors in neuropathic pain is poorly understood. In this study, we report that transcription factor (TF) ETS proto-oncogene 1 (ETS1) is required for the initiation and development of neuropathic pain. Sciatic nerve chronic constrictive injury (CCI, a clinical neuropathic pain model) increases ETS1 expression in the injured male mouse DRG. Blocking this upregulation alleviated CCI-induced mechanical allodynia and thermal hyperalgesia, with no apparent effect on locomotor function. Mimicking this upregulation results in the genesis of nociception hypersensitivity; mechanistically, nerve injury-induced ETS1 upregulation promotes the expression of histone deacetylase 1 (HDAC1, a key initiator of pain) via enhancing its binding activity to the HDAC1 promotor, leading to the elevation of spinal central sensitization, as evidenced by increased expression of p-ERK1/2 and GFAP in the dorsal spinal horn. It appears that the ETS1/HDAC1 axis in DRG may have a critical role in the development and maintenance of neuropathic pain, and ETS1 is a potential therapeutic target in neuropathic pain. [ABSTRACT FROM AUTHOR]

Epithelial-specific Maspin is widely known as a tumor suppressor. However, while the level of maspin expression is inversely correlated with tumor grade and stage, emerging clinical evidence shows a correlation between seemingly better differentiated tumor cells that express Maspin in both the nucleus and the cytoplasm, (n + c)Maspin, with a poor prognosis of many types of cancer. Biological studies demonstrate that Maspin plays an essential role in stem cell differentiation. In light of the recently established characterization of primed stem cells (P-SCs) in development, we propose, for the first time, that cancer stem cells (CSCs) also need to undergo priming (P-CSCs) before their transition to various progeny phenotypes. We envisage major differences in the steady state kinetics between P-SCs and P-CSCs. We further propose that P-CSCs of carcinoma are both marked and regulated by (n + c)Maspin. The concept of P-CSCs helps explain the apparent dichotomous relationships of (n + c)Maspin expression with cancer diagnosis and prognosis, and is supported by the evidence from mechanistic studies. We believe that the potential utility of (n + c)Maspin as a molecular marker of P-CSCs may significantly accelerate the advancement in our understanding of the genesis of tumor phenotypic plasticity in response to changes of tumor microenvironments (TME) or drug treatments. The vulnerabilities of the cellular state of (n + c)Maspin-expressing P-CSCs are also discussed as the rationale for future development of P-CSC-targeted chemotherapeutic and immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Angiotensin AT2-receptor signaling is atypical for a G-protein coupled receptor and incompletely understood. To obtain novel insights into AT2-receptor signaling, we mapped changes in the phosphorylation status of the entire proteome of human aortic endothelial cells in response to AT2-receptor stimulation.Methods: Phosphorylation status of human aortic endothelial cells after stimulation with C21 (1 µM; 0, 1, 3, 5, 20 minutes) was determined utilizing time-resolved quantitative phosphoproteomics. Specific changes in protein phosphorylation and acetylation were confirmed by Western Blotting. Functional tests included resazurin assay for cell proliferation, and caspase 3/7 luminescence assay or FACS analysis of annexin V expression for apoptosis.Results: AT2-receptor stimulation significantly altered the phosphorylation status of 172 proteins (46% phosphorylations, 54% dephosphorylations). Bioinformatic analysis revealed a cluster of phospho-modified proteins involved in antiproliferation and apoptosis. Among these proteins, HDAC1 (histone-deacetylase-1) was dephosphorylated at serine421/423 involving serine/threonine phosphatases. Resulting HDAC1 inhibition led to p53 acetylation and activation. AT2-receptor stimulation induced antiproliferation and apoptosis, which were absent when cells were co-incubated with the p53 inhibitor pifithrin-α, thus indicating p53-dependence of these AT2-receptor mediated functions.Conclusions: Contrary to the prevailing view that AT2-receptor signaling largely involves phosphatases, our study revealed significant involvement of kinases. HDAC1 inhibition and resulting p53 activation were identified as novel, AT2-receptor coupled signaling mechanisms. Furthermore, the study created an openly available dataset of AT2-receptor induced phospho-modified proteins, which has the potential to be the basis for further discoveries of currently unknown, AT2-receptor coupled signaling mechanisms. [ABSTRACT FROM AUTHOR]

Objective To investigate the promoting effect of histone deacetylase 1(HDAC1) expression on insulin resistance(IR) in nonalcoholic fatty liver disease(NAFLD) cells by establishing an HepG2 cell model of high fat-induced NAFLD. Methods HepG2 cells were divided into control group, model group(OA), and inhibitor group(OA+pyroxamide [an HDAC1 inhibitor]). CCK-8 assay was used to plot the standard growth curve of HepG2 cells and screen out the optimal drug concentration and action time of OA and pyroxamide; oil red O staining was used to compare the accumulation of lipid droplets in cells; an automatic biochemical analyzer was used to analyze the content of alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglyceride(TG), and total cholesterol(TC) in cells; quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of HDAC1 and insulin receptor substrate-1(IRS-1) in cells. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results OA treatment at a concentration of 0.25 mmol/L for 24 hours was the optimal concentration and duration of cell modeling, and treatment at a concentration of 20 μmol/L for 24 hours was the optimal administration concentration and duration of pyroxamide. Compared with the control group, the model group had significant increases in the content of ALT, AST, TG, and TC, and compared with the model group, the inhibitor group had significant reductions in the content of ALT, AST, TG, and TC(all P<0.05). The model group had significantly higher mRNA and protein expression levels of HDAC1 than the control group, while the inhibitor group had significantly lower expression levels than the model group(all P<0.05); the model group had significantly lower mRNA and protein expression levels of IRS-1 than the control group, while the inhibitor group had significantly higher expression levels than the model group(all P<0.05). Conclusion HDAC1 participates in the development and progression of NAFLD by inhibiting the expression of IRS-1 molecule and promoting IR, and the HDAC1 inhibitor pyroxamide can exert a protective effect on the liver by alleviating IR. [ABSTRACT FROM AUTHOR]

The study was performed to ascertain the mechanism of sodium butyrate (NaB) mediating the proliferative and invasive properties of oral squamous cell carcinoma (OSCC) cells. The cell proliferative, migrating, and invasive potentials were detected by CCK-8, colony formation, EdU, and Transwell assays. The expression of proliferation- and invasion-related proteins, HDAC1, and HSPB7 in OSCC cells were evaluated by western blot. Immunofluorescence was also performed to evaluate the HDAC1 expression. The enrichment of histone deacetylase HDAC1 in the promoter region of HSPB7 was assessed by the ChIP assay. In vivo growth of OSCC cells was measured by tumorigenesis in nude mice (n=18). The t-test was employed for comparisons of data between the two groups. One-way ANOVA was utilized for comparisons of data among multiple groups, and repeated-measures ANOVA for comparisons of data at different time points among groups, followed by Bonferroni post-hoc test. The data showed that HDAC1 expression was highly upregulated in OSCC cells compared to human normal oral keratinocytes (HNOKs) (p<0.0001), and NaB diminished the HDAC1 expression in OSCC cells. NaB restricted OSCC cell proliferative, migrating, and invasive capabilities by downregulating HDAC1. HSPB7 expression was downregulated in OSCC cells versus HNOKs (p<0.0001). HDAC1 inversely orchestrated the HSPB7 expression in OSCC cells through histone deacetylation modification, and NaB augmented the HSPB7 expression by inhibiting HDAC1. Moreover, NaB inhibited OSCC cell growth in vivo by elevating HSPB7 levels through the HDAC1 repression. In conclusion, NaB restrained cell proliferation and invasion in OSCC cells via HSPB7 upregulation by decreasing the HDAC1 expression. [ABSTRACT FROM AUTHOR]

Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Ɩ/ʎ (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.

Ribosome biogenesis in Saccharomyces cerevisiae involves a regulon of >200 genes (Ribi genes) coordinately regulated in response to nutrient availability and cellular growth rate. Two cis-acting elements called PAC and RRPE are known to mediate Ribi gene repression in response to nutritional downshift. Here, we show that most Ribi gene promoters also contain binding sites for one or more General Regulatory Factors (GRFs), most frequently Abf1 and Reb1, and that these factors are enriched in vivo at Ribi promoters. Abf1/Reb1/Tbf1 promoter association was required for full Ribi gene expression in rich medium and for its modulation in response to glucose starvation, characterized by a rapid drop followed by slow recovery. Such a response did not entail changes in Abf1 occupancy, but it was paralleled by a quick increase, followed by slow decrease, in Rpd3L histone deacetylase occupancy. Remarkably, Abf1 site disruption also abolished Rpd3L complex recruitment in response to starvation. Extensive mutational analysis of the DBP7 promoter revealed a complex interplay of Tbf1 sites, PAC and RRPE in the transcriptional regulation of this Ribi gene. Our observations point to GRFs as new multifaceted players in Ribi gene regulation both during exponential growth and under repressive conditions.

Histone deacetylases (HDACs) have been extensively studied as drug targets in neurodegenerative diseases, but less is known about their role in healthy neurons. We tested zinc-dependent HDACs using RNAi in Drosophila melanogaster and found memory deficits with RPD3 and HDAC6. We demonstrate that HDAC6 is required in both the larval and adult stages for normal olfactory memory retention. Neuronal expression of HDAC6 rescued memory deficits, and we demonstrate that the N-terminal deacetylase (DAC) domain is required for this ability. This suggests that deacetylation of synaptic targets associated with the first DAC domain, such as the active-zone scaffold Bruchpilot, is required for memory retention. Finally, electrophysiological experiments at the neuromuscular junction reveal that HDAC6 mutants exhibit a partial block of homeostatic plasticity, suggesting that HDAC6 may be required for the stabilization of synaptic strength. The learning deficit we observe in HDAC6 mutants could be a behavioral consequence of these synaptic defects.

The molecular mechanism underlying the promotion of fracture healing by mechanical stimuli remains unclear. The present study aimed to investigate the role of zinc finger protein 36 like 2 (ZFP36L2)-histone deacetylase 1 (HDAC1) axis on the osteogenic responses to moderate mechanical stimulation. Appropriate stimulation of fluid shear stress (FSS) was performed on MC3T3-E1 cells transduced with ZFP36L2 and HDAC1 recombinant adenoviruses, aiming to validate the influence of mechanical stress on the expression of ZFP36L2-HDAC1 and the osteogenic differentiation and mineralization. The results showed that moderate FSS stimulation significantly upregulated the expression of ZFP36L2 in MC3T3-E1 cells (p < 0.01). The overexpression of ZFP36L1 markedly enhanced the levels of osteogenic differentiation markers, including bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), Osterix, and collagen type I alpha 1 (COL1A1) (p < 0.01). ZFP36L2 accelerated the degradation of HDAC1 by specifically binding to its 3' UTR region, thereby fulfilling its function at the post-transcriptional regulatory gene level and promoting the osteogenic differentiation and mineralization fate of cells. Mechanical unloading notably diminished/elevated the expression of ZFP36L2/HDAC1, decreased bone mineral density and bone volume fraction, hindered the release of osteogenic-related factors and vascular endothelial growth factor in callus tissue (p < 0.01), and was detrimental to fracture healing. Collectively, proper stress stimulation plays a crucial role in facilitating osteogenesis through the promotion of ZFP36L2 and subsequent degradation of HDAC1. Targeting ZFP36L2-HDAC1 axis may provide promising insights to enhance bone defect healing. [Display omitted] • FSS stimulation up-regulates ZFP36L2 expression in MC3T3-E1 cells. • ZFP36L1 promotes osteogenic differentiation. • ZFP36L1 degrades HDAC1 mRNA to promote osteogenic differentiation. • Mechanical unloading retards fracture healing. • Mechanical unloading diminishes/elevates the expression of ZFP36L2/HDAC1. [ABSTRACT FROM AUTHOR]

Background: Histone deacetylase 1 (HDAC1) belongs to class I histone deacetylases, which are zinc‐dependent enzymes that remove the acetyl group from histones and other proteins providing epigenetic regulation of gene expression. It plays an important role in the hair follicle and epidermal homeostasis in addition to its immunomodulatory roles. Alopecia areata (AA) and acne vulgaris are common skin diseases in which epigenetic factors have been proposed. However, studies of epigenetic modifications in both diseases are quite limited. Objective: This study aimed at elucidation of HDAC1 deregulation in AA and acne vulgaris. Methods: A case‐control study was conducted on 76 participants: 25 patients with patchy alopecia areata, 26 patients with acne vulgaris and 25 healthy controls. Blood samples were collected for the measurement of HDAC1 level by ELISA. Results: A significant difference in the serum level of HDAC1 was found between the studied groups being highest in the AA group (P = 0.0001). It was significantly higher in the AA group than the acne vulgaris group (P = 0.0001). Conclusion: HDAC1 appears to be deregulated in patients with AA and acne vulgaris. This may suggest a potential therapeutic opportunity for HDAC inhibitors for the treatment of such diseases. [ABSTRACT FROM AUTHOR]

Abstract Researches pivoting on histone deacetylases (HDACs) in depression have been excessively conducted, but not much on HDAC1. Therein, the present study is launched to disclose the mechanism of HDAC1/microRNA (miR)-124-5p/neuropeptide Y (NPY) axis in depression. Sprague Dawley rats were stimulated by chronic unpredictable mild stress to establish depression models. Depressed rats were injected with inhibited HDAC1 or suppressed miR-124-5p to explore their roles in body weight, learning and memory abilities, oxidative stress and inflammation in serum and neurotransmitter expression in hippocampal tissues. MiR-124-5p, HDAC1 and NPY expression in the hippocampus were tested. The interactions of miR-124-5p, HDAC1 and NPY expression were also confirmed. Higher miR-124-5p and HDAC1 and lower NPY expression levels were found in the hippocampus of depressed rats. Inhibited miR-124-5p or suppressed HDAC1 attenuated learning and memory abilities and increased body weight of depressed rats. Knockdown of miR-124-5p or inhibition of HDAC1 suppressed oxidative stress and inflammation and promoted neurotransmitter expression of depressed rats. HDAC1 mediated miR-124-5p to regulate NPY. Knockdown of NPY abolished the protective effects of inhibited miR-124-5p on depressed rats. Our study illustrates that suppression of either miR-124-5p or HDAC1 up-regulates NPY to improve memory and learning abilities in depressed mice, which may update the existed knowledge of depression and provide a novel reference for treatment of depression.

Abstract Targeted anti‐cancer therapy selectively inhibits the growth of malignant cells by interfering with cancer‐specific signaling pathways, and inflicts minimal toxicity to normal tissues. Here, the current study demonstrates black phosphorus quantum dots (BPQDs) can target histone deacetylase 1 (HDAC1), which is overexpressed in multiple tumors and involved in cancer progression. The BPQDs inhibit HDAC1 activity and impair HDAC1‐mediated deacetylation of the mitotic spindle protein Eg5 in human renal cell carcinoma (RCC) cells, thereby disrupting the mitotic spindle structure and stalling cell cycle progression. Since HDAC1 regulates multiple aspects of cancer progression, BPQDs can neutralize the malignant potential of cancer cells by suppressing their proliferation and migration, and inducing apoptosis. Further in vitro assays demonstrate BPQDs significantly increase the sensitivity of RCC cells to the clinical chemotherapeutic agent, paclitaxel (PTX). Moreover, animal experiments also indicate the combined approach with both BPQDs and PTX displays better efficacy than PTX alone. These findings demonstrate that BPQDs have potential applications in targeted anti‐cancer therapy and can be more effectively treated with chemotherapy.

Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus causing acute intestinal infection in pigs, with high mortality often seen in neonatal pigs. The newborns rely on innate immune responses against invading pathogens because of lacking adaptive immunity. However, how PEDV disables the innate immunity of newborns toward severe infection remains unknown. We found that PEDV infection led to reduced expression of histone deacetylases (HDACs), especially HDAC1, in porcine IPEC-J2 cells. HDACs are considered important regulators of innate immunity. We hypothesized that PEDV interacts with certain host factors to regulate HDAC1 expression in favor of its replication. We show that HDAC1 acted as a negative regulator of PEDV replication in IPEC-J2 cells, as shown by chemical inhibition, gene knockout, and overexpression. A GC-box (GCCCCACCCCC) within the HDAC1 promoter region was identified for Sp1 binding in IPEC-J2 cells. Treatment of the cells with Sp1 inhibitor mithramycin A inhibited HDAC1 expression, indicating direct regulation of HDAC1 expression by Sp1. Of the viral proteins that were overexpressed in IPEC-J2 cells, the N protein was found to be present in the nuclei and more inhibitory to HDAC1 transcription. The putative nuclear localization sequence 261PKKNKSR267 contributed to its nuclear localization. The N protein interacted with Sp1 and interfered with its binding to the promoter region, thereby inhibiting its transcriptional activity for HDAC1 expression. Our findings reveal a novel mechanism of PEDV evasion of the host responses, offering implications for studying the infection processes of other coronaviruses. IMPORTANCE The enteric coronavirus porcine epidemic diarrhea virus (PEDV) causes fatal acute intestinal infection in neonatal pigs that rely on innate immune responses. Histone deacetylases (HDACs) play important roles in innate immune regulation. Our study found PEDV suppresses HDAC1 expression via the interaction of its N protein and porcine Sp1, which identified a novel mechanism of PEDV evasion of the host responses to benefit its replication. This study suggests that other coronaviruses, including SARS-CoV and SARS-CoV-2, also make use of their N proteins to intercept the host immune responses in favor of their infection. [ABSTRACT FROM AUTHOR]

Theileria and Babesia species are eukaryotic protozoan parasites classified under the order Piroplasmida of the phylum Apicomplexa. Tick vectors transmit these microorganisms in tropical and subtropical regions to a wide range of animals, including ruminants, causing fatal and life-threatening diseases such as bovine babesiosis and theileriosis. Resistance to commercially available drugs requires the search for new drug candidates. Histone deacetylase (HDAC) has a potential to be utilized as a drug target; therefore, it may be considered as an effective alternative. Previous studies revealed that HDAC inhibitors, identified for human use, show promising anti-parasitic effects. We have herein focused on the class I HDAC enzyme, HDAC1, of the Babesia and Theileria species to discover potential benzamide inhibitors by following a streamlined workflow of computer-aided drug design methodology. Molecular docking and molecular dynamics simulations revealed that benzamide derivatives stably interacted with the HDAC1 active site in both parasites as hypothesized. Furthermore, specific residue insertions at the entry point of the active site cleft of parasitic HDAC1 could enable ways to design parasite-specific drugs without adversely affecting host enzymes. [ABSTRACT FROM AUTHOR]

DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDAC) 1 to 3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell-cycle independent increased DNMT1 stability, and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter, and derepression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability. In summary, our study provides evidence for an important role of class I HDACs in controlling the stability of DNMT1 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention.

TLR4 signaling induces down-regulation of the bone morphogenic protein (BMP) and activin membrane-bound inhibitor (BAMBI), which enhances TGF-β signaling during hepatic stellate cell (HSC) activation. We investigated the mechanism by which TLR4 signaling down-regulates BAMBI expression in HSCs and found that TLR4- and TNF-α-mediated BAMBI down-regulation is dependent on regulation of BAMBI promoter activity through the interaction with NF-κBp50 and HDAC1 in HSCs. Bambi was predominantly expressed in HSCs, at high levels in quiescent HSCs but at low levels in in vivo-activated and LPS-stimulated HSCs. In human HSCs, BAMBI expression was down-regulated in response to LPS and TNF-α. A BAMBI reporter assay demonstrated that the regulatory element to repress BAMBI transcription is located between 3384 and 1560 bp upstream from the transcription start site. LPS stimulation down-regulated BAMBI expression in cells with NF-κBp65 knockdown. However, it failed to down-regulate BAMBI in cells with inactivation of NF-κB or NF-κBp50 silencing, indicating that NF-κBp50 is a factor for BAMBI down-regulation. ChIP analysis revealed that LPS and TNF-α induced binding of the NF-κBp50/p50 homodimer to the BAMBI promoter region. We also found that HDAC1 is bound to this region as part of the NF-κBp50-HDAC1 complex, repressing transcriptional activity of the BAMBI promoter. Finally, we confirmed that LPS does not repress BAMBI reporter activity using a BAMBI reporter construct with a mutation at 3166 bp upstream of the coding region. In summary, our study demonstrates that LPS- and TNF-α-induced NF-κBp50-HDAC1 interaction represses BAMBI transcriptional activity, which contributes to TLR4-mediated enhancement of TGF-β signaling in HSCs during liver fibrosis.

Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf) as a target of FUS-R521C-associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.

Hypoxia-ischemia brain damage (HIBD) is a neurological disorder occring in neonates, which is exacerbated by neuronal apoptosis. Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been proposed as a promising strategy for treating or preventing ischemia-related diseases. However, their mechanisms in HIBD remain unclear. Thus, we aimed to address the role of EV-derived microRNA (miR)-410 in HIBD. Neonatal HIBD mouse model was constructed using HI insult, from which neurons were isolated, followed by exposure to oxygen glucose deprivation (OGD). EVs were isolated from human umbilical cord (hUC)-derived MSCs. In silico analyses, dual-luciferase reporter gene and chromatin immunoprecipitation assays were adopted to determine relationships among miR-410, histone deacetylase 1 (HDAC1), early growth response protein 2 (EGR2), and B cell lymphoma/leukemia 2 (Bcl2). The functional roles of EV-derived miR-410 were determined using loss- and gain-of functions experiments, and by evaluating neuronal viability, cell-cycle distribution and neuronal apoptosis in vitro as well as modified neurological severity score (mNSS), edema formation, and cerebral infarction volume in vivo. hUC-MSCs-derived EVs protected against HIBD in vivo and inhibited the OGD-induced neuronal apoptosis in vitro. miR-410 was successfully delivered to neurons by hUC-MSCs-EVs and negatively targeted HDAC1, which inversely mediated the expression of EGR2/Bcl2. Upregulation of EV-derived miR-410 promoted the viability but inhibited apoptosis of neurons, which was reversed by HDAC1 overexpression. EV-derived miR-410 elevation reduced mNSS, edema formation, and cerebral infarction volume by increasing EGR2/Bcl2 expression through downregulating HDAC1 expression in vivo. In summary, EV-derived miR-410 impeded neuronal apoptosis by elevating the expression of EGR2/Bcl2 via HDAC1 downregulation, thereby providing a potential strategy for treating or preventing HIBD.

Defects in DNA repair have been extensively linked to neurodegenerative diseases, but the exact mechanisms remain poorly understood. We found that FUS, an RNA/DNA-binding protein that has been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, is important for the DNA damage response (DDR). The function of FUS in DDR involved a direct interaction with histone deacetylase 1 (HDAC1), and the recruitment of FUS to double-stranded break sites was important for proper DDR signaling. Notably, FUS proteins carrying familial ALS mutations were defective in DDR and DNA repair and showed a diminished interaction with HDAC1. Moreover, we observed increased DNA damage in human ALS patients harboring FUS mutations. Our findings suggest that an impaired DDR and DNA repair may contribute to the pathogenesis of neurodegenerative diseases linked to FUS mutations.

Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors.

Researches pivoting on histone deacetylases (HDACs) in depression have been excessively conducted, but not much on HDAC1. Therein, the present study is launched to disclose the mechanism of HDAC1/microRNA (miR)-124-5p/neuropeptide Y (NPY) axis in depression. Sprague Dawley rats were stimulated by chronic unpredictable mild stress to establish depression models. Depressed rats were injected with inhibited HDAC1 or suppressed miR-124-5p to explore their roles in body weight, learning and memory abilities, oxidative stress and inflammation in serum and neurotransmitter expression in hippocampal tissues. MiR-124-5p, HDAC1 and NPY expression in the hippocampus were tested. The interactions of miR-124-5p, HDAC1 and NPY expression were also confirmed. Higher miR-124-5p and HDAC1 and lower NPY expression levels were found in the hippocampus of depressed rats. Inhibited miR-124-5p or suppressed HDAC1 attenuated learning and memory abilities and increased body weight of depressed rats. Knockdown of miR-124-5p or inhibition of HDAC1 suppressed oxidative stress and inflammation and promoted neurotransmitter expression of depressed rats. HDAC1 mediated miR-124-5p to regulate NPY. Knockdown of NPY abolished the protective effects of inhibited miR-124-5p on depressed rats. Our study illustrates that suppression of either miR-124-5p or HDAC1 up-regulates NPY to improve memory and learning abilities in depressed mice, which may update the existed knowledge of depression and provide a novel reference for treatment of depression. [ABSTRACT FROM AUTHOR]

Targeted anti‐cancer therapy selectively inhibits the growth of malignant cells by interfering with cancer‐specific signaling pathways, and inflicts minimal toxicity to normal tissues. Here, the current study demonstrates black phosphorus quantum dots (BPQDs) can target histone deacetylase 1 (HDAC1), which is overexpressed in multiple tumors and involved in cancer progression. The BPQDs inhibit HDAC1 activity and impair HDAC1‐mediated deacetylation of the mitotic spindle protein Eg5 in human renal cell carcinoma (RCC) cells, thereby disrupting the mitotic spindle structure and stalling cell cycle progression. Since HDAC1 regulates multiple aspects of cancer progression, BPQDs can neutralize the malignant potential of cancer cells by suppressing their proliferation and migration, and inducing apoptosis. Further in vitro assays demonstrate BPQDs significantly increase the sensitivity of RCC cells to the clinical chemotherapeutic agent, paclitaxel (PTX). Moreover, animal experiments also indicate the combined approach with both BPQDs and PTX displays better efficacy than PTX alone. These findings demonstrate that BPQDs have potential applications in targeted anti‐cancer therapy and can be more effectively treated with chemotherapy. [ABSTRACT FROM AUTHOR]

Many disease states require multiple drugs to inhibit multiple targets for their effective treatment/management, i.e. a drug cocktail regimen, or "polypharmacy". Polypharmacology, in contrast, is the development of single agents that can inhibit multiple targets. Each strategy is associated with advantages and disadvantages. Motivated by promising clinical trial data for the treatment of multiple myeloma with the combination of the HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity. In general, previously reported specificity determinants of monovalent HDAC1/6 inhibitors were preserved in our dual HDAC/proteasome inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background/aim: Only a few studies have examined the expression of nucleosome remodeling and deacetylase complex in endometrial carcinoma (EC). The aim of this study was to analyze the expressions of histone deacetylase (HDAC1), HDAC2, and chromodomain helicase DNA-binding protein 4 (CHD4) in EC., Patients and Methods: Sixty cases of EC were categorized into two clusters based on the expression levels of the three proteins., Results: Cluster 1 (C1) exhibited elevated expressions of HDAC2 and CHD4 compared with cluster 2 (C2). Notably, 75% of cases in C2 represented non-aggressive histological types, whereas 37.5% of cases in C1 manifested aggressive types. C2 exclusively comprised pathological tumor stage 1 (pT1) tumors, whereas C1 included pT2 and pT3 tumors. In C1, 25% of cases displayed aberrant p53 expression, contrasting with the absence of such expression in C2. Furthermore, only one patient in C2 experienced disease recurrence, whereas 20.8% of patients in C1 developed recurrent tumors., Conclusion: High HDAC2 and CHD4 expression may be associated with adverse clinicopathological characteristics in EC. Further studies are needed to validate these results., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We have previously demonstrated amelioration of Huntington's disease (HD)-related phenotypes in R6/2 transgenic mice in response to treatment with the novel histone deacetylase (HDAC) inhibitor 4b. Here we have measured the selectivity profiles of 4b and related compounds against class I and class II HDACs and have tested their ability to restore altered expression of genes related to HD pathology in mice and to rescue disease effects in cell culture and Drosophila models of HD. R6/2 transgenic and wild-type (wt) mice received daily injections of HDAC inhibitors for 3 days followed by real-time PCR analysis to detect expression differences for 13 HD-related genes. We find that HDACi 4b and 136, two compounds showing high potency for inhibiting HDAC3 were most effective in reversing the expression of genes relevant to HD, including Ppp1r1b, which encodes DARPP-32, a marker for medium spiny striatal neurons. In contrast, compounds targeting HDAC1 were less effective at correcting gene expression abnormalities in R6/2 transgenic mice, but did cause significant increases in the expression of selected genes. An additional panel of 4b-related compounds was tested in a Drosophila model of HD and in STHdhQ111 striatal cells to further distinguish HDAC selectivity. Significant improvement in huntingtin-elicited Drosophila eye neurodegeneration in the fly was observed in response to treatment with compounds targeting human HDAC1 and/or HDAC3. In STHdhQ111 striatal cells, the ability of HDAC inhibitors to improve huntingtin-elicited metabolic deficits correlated with the potency at inhibiting HDAC1 and HDAC3, although the IC50 values for HDAC1 inhibition were typically 10-fold higher than for inhibition of HDAC3. Assessment of HDAC protein localization in brain tissue by Western blot analysis revealed accumulation of HDAC1 and HDAC3 in the nucleus of HD transgenic mice compared to wt mice, with a concurrent decrease in cytoplasmic localization, suggesting that these HDACs contribute to a repressive chromatin environment in HD. No differences were detected in the localization of HDAC2, HDAC4 or HDAC7. These results suggest that inhibition of HDACs 1 and 3 can relieve HD-like phenotypes in model systems and that HDAC inhibitors targeting these isotypes might show therapeutic benefit in human HD.

There is an urgent unmet need to develop new therapeutics for lung squamous cell carcinoma (LSCC) as the current gold standard treatment regimens are dominated by chemotherapy. In this study, we observed the treatment effects of the natural compound tambulin on LSCC and explored its mechanism of action. LSCC cell lines H226 and H520 were cultured in vitro to observe the effects of tambulin on cell proliferation and apoptosis. Western blotting was used to detect the expression of histone deacetylase 1 (HDAC1) and apoptosis-related proteins. Cell derived xenografts (CDX) of H226 and H520 in nude mice were established to examine the inhibitory effects of tambulin in vivo. Results showed that tambulin inhibited the proliferation of H226 and H520 cells in a dose-dependent manner and inhibited the growth of CDX tumors. Tambulin also promoted the apoptosis of H226 and H520 cells, up-regulated the protein expression of cleaved caspase-3, cleaved caspase-9 and Bax, and down-regulated HDAC1 and Bcl-2 protein expression. In support of this, immunohistochemical analysis of CDX tumors from mice treated with tambulin showed increased expression of cleaved caspase-3 and Bax, while the expression of HDAC1 and Bcl-2 were decreased. What’s more, when HDAC1 was over-expressed via adenovirus transduction in H226 or H520 cells, the effects of tambulin were significantly attenuated. Interestingly, we found that combining tambulin with cisplatin treatment in CDX models was more effective than single drug treatment, suggesting that tambulin may enhance the sensitivity of LSCC to cisplatin. Taken together, this study proves that tambulin has a definite therapeutic effect on LSCC. Mechanistically, tambulin downregulates HDAC1, which in turn regulates the Bcl-2/caspase signaling pathway and promotes cancer cell apoptosis.

MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that regulate gene expression by repressing translation or triggering the degradation of complementary mRNA sequences. Certain miRNAs have been shown to function as integral components of the p53 and/or retinoblastoma (Rb) regulatory networks. As such, miRNA dysregulation can have a profound effect on cancer development. Previous studies have shown that miR-449a is down-regulated in human prostate cancer tissue and possesses potential tumor suppressor function. In the present study, we identify miR-449a-mediated growth arrest in prostate cancer cells is dependent on the Rb protein. We show that mutant Rb prostate cancer cells (DU- 145) are resistant to cell cycle arrest and cellular senescence induced by miR- 449a, while overexpression of wild-type Rb in DU-145 sublines (DU-1.1 and B5) restores miR-449a function. In silico analysis of 3'UTR regions reveal a putative miR-449a target site in the transcript of Cyclin D1 (CCND1); an oncogene involved in directly regulating Rb activity and cell cycle progression. Luciferase 3'UTR reporter constructs and inhibitory oligonucleotides confirm that Cyclin D1 is a direct downstream target of miR-449a. We also reveal that miR-449a suppresses Rb phosphorylation through the knockdown of Cyclin D1 and previously validated target HDAC1. By targeting genes involved in controlling Rb activity, miR- 449a regulates growth and senescence in an Rb-dependent manner. These data indicate that miR-449a is a miRNA component of the Rb pathway and its tumor suppressor-like effects, in part, depends on Rb status in prostate cancer cells.

There is an urgent unmet need to develop new therapeutics for lung squamous cell carcinoma (LSCC) as the current gold standard treatment regimens are dominated by chemotherapy. In this study, we observed the treatment effects of the natural compound tambulin on LSCC and explored its mechanism of action. LSCC cell lines H226 and H520 were cultured in vitro to observe the effects of tambulin on cell proliferation and apoptosis. Western blotting was used to detect the expression of histone deacetylase 1 (HDAC1) and apoptosis-related proteins. Cell derived xenografts (CDX) of H226 and H520 in nude mice were established to examine the inhibitory effects of tambulin in vivo. Results showed that tambulin inhibited the proliferation of H226 and H520 cells in a dose-dependent manner and inhibited the growth of CDX tumors. Tambulin also promoted the apoptosis of H226 and H520 cells, up-regulated the protein expression of cleaved caspase-3, cleaved caspase-9 and Bax, and down-regulated HDAC1 and Bcl-2 protein expression. In support of this, immunohistochemical analysis of CDX tumors from mice treated with tambulin showed increased expression of cleaved caspase-3 and Bax, while the expression of HDAC1 and Bcl-2 were decreased. What's more, when HDAC1 was over-expressed via adenovirus transduction in H226 or H520 cells, the effects of tambulin were significantly attenuated. Interestingly, we found that combining tambulin with cisplatin treatment in CDX models was more effective than single drug treatment, suggesting that tambulin may enhance the sensitivity of LSCC to cisplatin. Taken together, this study proves that tambulin has a definite therapeutic effect on LSCC. Mechanistically, tambulin downregulates HDAC1, which in turn regulates the Bcl-2/caspase signaling pathway and promotes cancer cell apoptosis. [ABSTRACT FROM AUTHOR]

We studied the effect of histone deacetylase 1 (HDAC1) inhibition on titin content and expression of TTN gene in rat m. soleus after 3-day gravitational unloading. Male Wistar rats weighing 210±10 g were randomly divided into 3 groups: control, 3-day hindlimb suspension, and 3-day hindlimb suspension and injection of HDAC1 inhibitor CI-994 (1 mg/kg/day). In hindlimb-suspended rats, the muscle weight/animal body weight ratio was reduced by 13.8% (p<0.05) in comparison with the control, which attested to the development of atrophic changes in the soleus muscle. This was associated with a decrease in the content of NT-isoform of intact titin-1 by 28.6% (p˂0.05) and an increase in TTN gene expression by 1.81 times (p˂0.05) in the soleus muscle. Inhibition of HDAC1 by CI-994 during 3-day hindlimb suspension prevented the decrease in titin content and development of atrophy in rat soleus muscle. No significant differences in the TTN gene expression from the control were found. These results can be used when finding the ways of preventing or reducing the negative changes in the muscle caused by gravitational unloading. [ABSTRACT FROM AUTHOR]

The present study analyzed the expression of the histone deacetylase (HDAC) 1, 2 and 3 in primary esophageal squamous cell carcinoma (ESCC) samples and how their levels correlate with clinicopathological parameters. ESCC patients (n=88) in the present study had received no previous treatment before undergoing surgical excision. The mRNA expression of HDAC1, -2 and -3 were detected by semi-quantified PCR in ESCC samples and distal normal samples. The relationship of HDAC1, -2 and -3 expression with clinicopathological parameters was analyzed by χ2 test. The correlation among these HDACs was analyzed by Pearson's correlation test. Compared with distal normal tissues, ESCC samples had higher expression of HDAC1, but not HDAC2 or HDAC3 (P<0.05). The expression of HDACs was different between Kazak and Han ethnicities. The expression of HDAC2 was correlated with invasion depth (P<0.05), but not with sex, age, metastasis, or the degree of tumor differentiation (P>0.05). There was no association between HDAC1 or HDAC3 and clinicopathological parameters (P>0.05). For the Kazak and Han ethnicities, HDAC1 expression was present in male patients, patients with well/moderate differentiated ESCC and T3 and T4 ESCC (P<0.01). HDAC1 in patients aged <60 was associated with ethnicity (P<0.05). HDAC2 expression was different in positive LN metastasis, well/moderate differentiation and T3 and T4 ESCC (P<0.01). HDAC3 expression in male patients, patients with negative LN metastasis and well/moderate differentiation ESCC was associated with ethnicity (P<0.05). Additionally, the expression levels of HDAC1, -2 and -3 did not correlate with each other. Thus, HDAC1 expression may be used as a risk factor for ESCC and HDAC2 levels may be used to predict invasion depth. The expression of HDAC1, -2 and -3 has ethnic differences. [ABSTRACT FROM AUTHOR]