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Acute lung injury (ALI) and its severe counterpart, acute respiratory distress syndrome (ARDS), are critical respiratory conditions with high mortality rates due primarily to acute and intense pulmonary inflammation. Despite significant research advances, effective pharmacological treatments for ALI and ARDS remain unavailable, highlighting an urgent need for therapeutic innovation. Notably, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the irreversible progression of fibrosis, which is initiated by repeated damage to the alveolar epithelium and leads to excessive extracellular matrix deposition. This condition is further complicated by dysregulated tissue repair and fibroblast dysfunction, exacerbating tissue remodeling processes and promoting progression to terminal pulmonary fibrosis. Similar to that noted for ALI and ARDS, treatment options for IPF are currently limited, with no specific drug therapy providing a cure. Histone deacetylase 3 (HDAC3), a notable member of the HDAC family with four splice variants (HD3a, -b, -g, and -d), plays multiple roles. HDAC3 regulates gene transcription through histone acetylation and adjusts nonhistone proteins posttranslationally, affecting certain mitochondrial and cytoplasmic proteins. Given its unique structure, HDAC3 impacts various physiological processes, such as inflammation, apoptosis, mitochondrial homeostasis, and macrophage polarization. This article explores the intricate role of HDAC3 in ALI/ARDS and IPF and evaluates its therapeutic potential the treatment of these severe pulmonary conditions. [ABSTRACT FROM AUTHOR]

Abstract Ischemia-induced retinopathy is a hallmark finding of common visual disorders including diabetic retinopathy (DR) and central retinal artery and vein occlusions. Treatments for ischemic retinopathies fail to improve clinical outcomes and the design of new therapies will depend on understanding the underlying disease mechanisms. Histone deacetylases (HDACs) are an enzyme class that removes acetyl groups from histone and non-histone proteins, thereby regulating gene expression and protein function. HDACs have been implicated in retinal neurovascular injury in preclinical studies in which nonspecific HDAC inhibitors mitigated retinal injury. Histone deacetylase 3 (HDAC3) is a class I histone deacetylase isoform that plays a central role in the macrophage inflammatory response. We recently reported that myeloid cells upregulate HDAC3 in a mouse model of retinal ischemia-reperfusion (IR) injury. However, whether this cellular event is an essential contributor to retinal IR injury is unknown. In this study, we explored the role of myeloid HDAC3 in ischemia-induced retinal neurovascular injury by subjecting myeloid-specific HDAC3 knockout (M-HDAC3 KO) and floxed control mice to retinal IR. The M-HDAC3 KO mice were protected from retinal IR injury as shown by the preservation of inner retinal neurons, vascular integrity, and retinal thickness. Electroretinography confirmed that this neurovascular protection translated to improved retinal function. The retinas of M-HDAC3 KO mice also showed less proliferation and infiltration of myeloid cells after injury. Interestingly, myeloid cells lacking HDAC3 more avidly engulfed apoptotic cells in vitro and after retinal IR injury in vivo compared to wild-type myeloid cells, suggesting that HDAC3 hinders the reparative phagocytosis of dead cells, a process known as efferocytosis. Further mechanistic studies indicated that although HDAC3 KO macrophages upregulate the reparative enzyme arginase 1 (A1) that enhances efferocytosis, the inhibitory effect of HDAC3 on efferocytosis is not solely dependent on A1. Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult.

Histone deacetylase 3 (HDAC3) is a crucial epigenetic modulator essential for various developmental and physiological functions. Although its dysfunction is increasingly recognized in abnormal phenotypes, to our knowledge, there have been no established reports of human diseases directly linked to HDAC3 dysfunction. Using trio exome sequencing and extensive phenotypic analysis, we correlated heterozygous de novo variants in HDAC3 with a neurodevelopmental disorder having variable clinical presentations, frequently associated with intellectual disability, developmental delay, epilepsy, and musculoskeletal abnormalities. In a cohort of six individuals, we identified missense variants in HDAC3 (c.277G>A [p.Asp93Asn], c.328G>A [p.Ala110Thr], c.601C>T [p.Pro201Ser], c. 797T>C [p.Leu266Ser], c.799G>A [p.Gly267Ser], and c.1075C>T [p.Arg359Cys]), all located in evolutionarily conserved sites and confirmed as de novo. Experimental studies identified defective deacetylation activity in the p.Asp93Asn, p.Pro201Ser, p.Leu266Ser, and p.Gly267Ser variants, positioned near the enzymatic pocket. In addition, proteomic analysis employing co-immunoprecipitation revealed that the disrupted interactions with molecules involved in the CoREST and NCoR complexes, particularly in the p.Ala110Thr variant, consist of a central pathogenic mechanism. Moreover, immunofluorescence analysis showed diminished nuclear to cytoplasmic fluorescence ratio in the p.Ala110Thr, p.Gly267Ser, and p.Arg359Cys variants, indicating impaired nuclear localization. Taken together, our study highlights that de novo missense variants in HDAC3 are associated with a broad spectrum of neurodevelopmental disorders, which emphasizes the complex role of HDAC3 in histone deacetylase activity, multi-protein complex interactions, and nuclear localization for proper physiological functions. These insights open new avenues for understanding the molecular mechanisms of HDAC3 -related disorders and may inform future therapeutic strategies. [Display omitted] Yoon et al. identify de novo missense variants in HDAC3 that are associated with neurodevelopmental disorders with variable clinical features. Characterization of these variants focusing on their functions in histone deacetylation, multi-protein complex interactions, and nuclear localization highlights the multifaceted role of HDAC3 in human physiology and diseases. [ABSTRACT FROM AUTHOR]

Ischemia-induced retinopathy is a hallmark finding of common visual disorders including diabetic retinopathy (DR) and central retinal artery and vein occlusions. Treatments for ischemic retinopathies fail to improve clinical outcomes and the design of new therapies will depend on understanding the underlying disease mechanisms. Histone deacetylases (HDACs) are an enzyme class that removes acetyl groups from histone and non-histone proteins, thereby regulating gene expression and protein function. HDACs have been implicated in retinal neurovascular injury in preclinical studies in which nonspecific HDAC inhibitors mitigated retinal injury. Histone deacetylase 3 (HDAC3) is a class I histone deacetylase isoform that plays a central role in the macrophage inflammatory response. We recently reported that myeloid cells upregulate HDAC3 in a mouse model of retinal ischemia-reperfusion (IR) injury. However, whether this cellular event is an essential contributor to retinal IR injury is unknown. In this study, we explored the role of myeloid HDAC3 in ischemia-induced retinal neurovascular injury by subjecting myeloid-specific HDAC3 knockout (M-HDAC3 KO) and floxed control mice to retinal IR. The M-HDAC3 KO mice were protected from retinal IR injury as shown by the preservation of inner retinal neurons, vascular integrity, and retinal thickness. Electroretinography confirmed that this neurovascular protection translated to improved retinal function. The retinas of M-HDAC3 KO mice also showed less proliferation and infiltration of myeloid cells after injury. Interestingly, myeloid cells lacking HDAC3 more avidly engulfed apoptotic cells in vitro and after retinal IR injury in vivo compared to wild-type myeloid cells, suggesting that HDAC3 hinders the reparative phagocytosis of dead cells, a process known as efferocytosis. Further mechanistic studies indicated that although HDAC3 KO macrophages upregulate the reparative enzyme arginase 1 (A1) that enhances efferocytosis, the inhibitory effect of HDAC3 on efferocytosis is not solely dependent on A1. Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult. [ABSTRACT FROM AUTHOR]

Histone deacetylase 3 (HDAC3) is a member of the histone deacetylase family that has emerged as a crucial target in the quest for novel therapeutic interventions against various complex diseases, including cancer. The repositioning of FDAapproved drugs presents a promising avenue for the rapid discovery of potential HDAC3 inhibitors. In this study, we performed a structure-based virtual screening of FDA-approved drugs obtained from DrugBank. Candidate hits were selected based on their binding affinities and interactions with HDAC3. These promising hits were then subjected to a comprehensive assessment of their biological properties and drug profiles. Our investigation identified two FDA-approved drugs, Imatinib and Carpipramine, characterized by their exceptional affinity and specificity for the binding pocket of HDAC3. These molecules demonstrated a strong preference for HDAC3 binding site and formed interactions with functionally significant residues within the active site pocket. To gain deeper insights into the binding dynamics, structural stability, and interaction mechanisms, we performed molecular dynamics (MD) simulations spanning 300 nanoseconds (ns). The results of MD simulations indicated that Imatinib and Carpipramine stabilized the structure of HDAC3 and induced fewer conformational changes. Taken together, the findings from this study suggest that Imatinib and Carpipramine may offer significant therapeutic potential for treating complex diseases, especially cancer. [ABSTRACT FROM AUTHOR]

Histone deacetylase 3 (HDAC3) is an epigenetic modification enzyme, which participates in the occurrence and development of atherosclerosis (As). It is significant to search for effective HDAC3 inhibitors for the treatment of atherosclerosis. This article reviews the relationship between HDAC3 and atherosclerosis, the latest research progress of HDAC3 inhibitors, and the therapeutic effects of some traditional Chinese medicine on cardiovascular diseases by inhibiting HDAC3. It aims to provide new ideas for developing anti-atherosclerotic drugs targeting HDAC3. [ABSTRACT FROM AUTHOR]

Proliferative vitreoretinopathy(PVR) is a type of fibrotic eye disease with a poor clinical prognosis. Increasing evidence has shown that the primary pathological mechanism of PVR is the epithelial-mesenchymal transition(EMT) of retinal pigment epithelium(RPE) cells. Histone deacetylase 3(HDAC3) is a crucial enzyme involved in regulating the acetylation level of proteins. Several studies have reported associations between HDAC3 levels and EMT in various tumors; however, the specific effect of HDAC3 on PVR remains largely unknown. The current study found that HDAC3 was highly expressed in both human PVR membranes and experimental PVR. In vivo, silencing HDAC3 in RPE cells reduced their ability to develop experimental PVR through suppression of EMT. In vitro, inhibition of HDAC3 in RPE cells suppressed EGF-mediated cell proliferation, migration, and EMT. Additionally, overexpression of HDAC3 in RPE cells promoted cell proliferation, migration, and EMT. Mechanistically, the results of chromatin immunoprecipitation(ChIP) and luciferase assays revealed a direct binding of the transcription factor MAZ to the promoter region of HDAC3, thereby promoting its transcription. Furthermore, It was demonstrated that HDAC3 facilitated EMT by interacting with AKT and contributing to its deacetylation. In summary, our findings indicated the involvement of HDAC3 in the EMT of RPE cells, as well as its role in PVR through the regulation of the AKT pathway. These results suggested that targeting HDAC3 could be a potential strategy for preventing and treating PVR.

Histone deacetylase 3 (HDAC3) is a member of the histone deacetylase family that has emerged as a crucial target in the quest for novel therapeutic interventions against various complex diseases, including cancer. The repositioning of FDA-approved drugs presents a promising avenue for the rapid discovery of potential HDAC3 inhibitors. In this study, we performed a structure-based virtual screening of FDA-approved drugs obtained from DrugBank. Candidate hits were selected based on their binding affinities and interactions with HDAC3. These promising hits were then subjected to a comprehensive assessment of their biological properties and drug profiles. Our investigation identified two FDA-approved drugs, Imatinib and Carpipramine, characterized by their exceptional affinity and specificity for the binding pocket of HDAC3. These molecules demonstrated a strong preference for HDAC3 binding site and formed interactions with functionally significant residues within the active site pocket. To gain deeper insights into the binding dynamics, structural stability, and interaction mechanisms, we performed molecular dynamics (MD) simulations spanning 300 nanoseconds (ns). The results of MD simulations indicated that Imatinib and Carpipramine stabilized the structure of HDAC3 and induced fewer conformational changes. Taken together, the findings from this study suggest that Imatinib and Carpipramine may offer significant therapeutic potential for treating complex diseases, especially cancer.

Background: The inflammation and immune response contribute to ischemic stroke pathology. Damaged brain cells release inflammatory substances to activate the immune system in the acute phase of stroke, including altering the interferon signaling pathway. However, the involvement of histone deacetylation in stroke remains unclear. Methods: To investigate whether histone deacetylation modulation could regulate the interferon signaling pathway and mediate the pathogenic changes after stroke, the middle cerebral artery occlusion (MCAO) mouse model was treated with histone deacetylase 3 (HDAC3) inhibitor and RGFP966. Additionally, a series of approaches, including middle cerebral artery occlusion (MCAO), real-time polymerase chain reaction (PCR), western blot, 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavioral experiments, and confocal imaging were utilized. Results: It is observed that RGFP966 pretreatment could lead to better outcomes in the MCAO mouse model, including the decrease of infarction volumes, the amelioration of post-stroke anxiety-like behavior, and the relief of inflammatory responses. Furthermore, we found that RGFP966 could counteract the hyperactivation of the interferon signaling pathway and the excessive expression of Z-DNA Binding Protein 1 (ZBP1) in microglia. Conclusions: We demonstrated a novel mechanism that HDAC3 inhibition could ameliorate the pathological injury after ischemic stroke by downregulating the ZBP1/phosphorylated Interferon Regulatory Factor 3 (p-IRF3) pathway. Thus, these data provide a new promising target for therapies for ischemic stroke. [ABSTRACT FROM AUTHOR]

Background and purpose: Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression. Experimental approach: Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography. Key results: HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. Conclusions and implications: Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress–activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology; however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.

Objective: It has been demonstrated the efficacy of histone deacetylase 3 (HDAC3) in diabetes. Nevertheless, the function of HDAC3 in diabetic retinopathy (DR) remained largely obscure. Here, we investigated the HDAC3 effects in DR mice through the microRNA (miR)-296-5p/G protein subunit alpha i2 (GNAI2) axis. Methods: The mice diabetes model was established. HDAC3, GNAI2 and miR-296-5p levels in retina tissues of DR mice were evaluated. The weight, blood glucose, Evans blue leakage in DR mice, apoptosis of retinal ganglion cells, vascular endothelial growth factor (VEGF) and malondialdehyde (MDA) contents and superoxide dismutase (SOD) activity in DR mice were detected after miR-296-5p elevation or HDAC3 depletion. The relations among HDAC3, miR-296-5p and GNAI2 were validated. Results: HDAC3 and GNAI2 expressed at a high level while miR-296-5p expressed at a low level in retina tissues of DR mice. Restoring miR-296-5p or depleting HDAC3 reduced Evans blue leakage in DR mice, attenuated apoptosis of retinal ganglion cells, reduced VEGF and MDA, and enhanced SOD activity in serum and retinal tissues of DR mice. HDAC3 repressed miR-296-5p expression by binding to its promoter region, thereby enhancing GNAI2 expression. Conclusion: Depleting HDAC3 or restoring miR-296-5p suppresses apoptosis of retinal ganglion cells of DR mice via down-regulating GNAI2.

The key role of histone deacetylases (HDAC) in the regulation of the cellular response to infection with the hepatitis C virus (HCV) was first demonstrated in 2008. When studying the metabolism of iron in the liver tissues of patients with chronic hepatitis C, the authors found that the expression of the hepcidin gene (HAMP), a hormone regulator of iron export, is markedly reduced in hepatocytes under conditions of oxidative stress caused by viral infection. HDAC were involved in the regulation of hepcidin expression through the control of acetylation level of histones and transcription factors, primarily STAT3, associated with the HAMP promoter. The purpose of this review was to summarize current data on the functioning of the HCV–HDAC3–STAT3–HAMP regulatory circuit as an example of a well-characterized interaction between the virus and the epigenetic apparatus of the host cell. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by progressive and irreversible lung scarring associated with persistent activation of fibroblasts. Epigenetics could integrate diverse microenvironmental signals, such as stiffness, to direct persistent fibroblast activation. Histone modifications by deacetylases (HDAC) may play an essential role in the gene expression changes involved in the pathological remodeling of the lung. Particularly, HDAC3 is crucial for maintaining chromatin and regulating gene expression, but little is known about its role in IPF. In the study, control and IPF-derived fibroblasts were used to determine the influence of HDAC3 on chromatin remodeling and gene expression associated with IPF signature. Additionally, the cells were grown on hydrogels to mimic the stiffness of a fibrotic lung. Our results showed a decreased HDAC3 in the nucleus of IPF fibroblasts, which correlates with changes in nucleus size and heterochromatin loss. The inhibition of HDAC3 with a pharmacological inhibitor causes hyperacetylation of H3K9 and provokes an increased expression of Col1A1, ACTA2, and p21. Comparable results were found in hydrogels, where matrix stiffness promotes the loss of nuclear HDAC3 and increases the profibrotic signature. Finally, latrunculin b was used to confirm that changes by stiffness depend on the mechanotransduction signals. Together, these results suggest that HDAC3 could be a link between epigenetic mechanisms and the fibrotic microenvironment. [ABSTRACT FROM AUTHOR]

Sepsis is one common cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which is closely associated with high mortality in intensive care units (ICU). Histone deacetylase 3 (HDAC3) serves as an important epigenetic modifying enzyme which could affect chromatin structure and transcriptional regulation. Here, we explored the effects of HDAC3 in type II alveolar epithelial cells (AT2) on lipopolysaccharide (LPS)-induced ALI and shed light on potential molecular mechanisms. We generated ALI mouse model with HDAC3 conditional knockout mice (Sftpc-cre; Hdac3f/f) in AT2 and the roles of HDAC3 in ALI and epithelial barrier integrity were investigated in LPS-treated AT2. The levels of HDAC3 were significantly upregulated in lung tissues from mice with sepsis and in LPS-treated AT2. HDAC3 deficiency in AT2 not only decreased inflammation, apoptosis, and oxidative stress, but also maintained epithelial barrier integrity. Meanwhile, HDAC3 deficiency in LPS-treated AT2 preserved mitochondrial quality control (MQC), evidenced by the shift of mitochondria from fission into fusion, decreased mitophagy, and improved fatty acid oxidation (FAO). Mechanically, HDAC3 promoted the transcription of Rho-associated protein kinase 1 (ROCK1) in AT2. In the context of LPS stimulation, the upregulated ROCK1 elicited by HDAC3 could be phosphorylated by Rho-associated (RhoA), thus disturbing MQC and triggering ALI. Furthermore, we found that forkhead box O1 (FOXO1) was one of transcription factors of ROCK1. HDAC3 directly decreased the acetylation of FOXO1 and promoted its nuclear translocation in LPS-treated AT2. Finally, HDAC3 inhibitor RGFP966 alleviated epithelial damage and improved MQC in LPS-treated AT2. Altogether, HDAC3 deficiency in AT2 alleviated sepsis-induced ALI by preserving mitochondrial quality control via FOXO1-ROCK1 axis, which provided a potential strategy for the treatment of sepsis and ALI.

Abstract Background Deacetylation of histones by histone deacetylase 3 (HDAC3) acts importantly in modulating apoptosis, DNA damage and cellular progression. Herein, we aimed to unravel the functional role of HDAC3 in a lethal disease, esophageal squamous cell carcinoma (ESCC). Methods The expression of HDAC3 in clinically collected ESCC tissues was determined by RT-qPCR and immunohistochemistry. As revealed from bioinformatics analysis, the putative relations between HDAC3 and microRNA-494 (miR-494) and between miR-494 and transforming growth factor beta (TGFβ)-inducing factor 1 (TGIF1) were further verified by chromatin immunoprecipitation and dual-luciferase reporter gene assay. Functional roles of shRNA-mediated depletion of HDAC3, miR-494 mimic and overexpressed TGIF1 were explored by gain- and loss-of-function assays with regard to ESCC cell biological behaviors. A nude mouse model of ESCC was developed for in vivo validation. Results HDAC3 was highly expressed in ESCC tissues, suggestive of poor prognosis while TGIF1 was upregulated and miR-494 was downregulated. Mechanistic investigation revealed that HDAC3 inhibited miR-494 expression and TGIF1 was a direct target of miR-494. Furthermore, silencing HDAC3 or overexpressing miR-494 was demonstrated to suppress aggressive phenotypes of ESCC cells both in vitro through the activated TGFβ signaling pathway and in vivo, while TGIF1 overexpression induced opposite results. Conclusion Collectively, our findings provided demonstration regarding the oncogenic property of HDAC3 in ESCC via the miR-494/TGIF1/TGFβ axis.

Insect development requires genes to be expressed in strict spatiotemporal order. The dynamic regulation of genes involved in insect development is partly orchestrated by the histone acetylation–deacetylation via histone acetyltransferases (HATs) and histone deacetylases (HDACs). Although histone deacetylase 3 (HDAC3) is required for mice during early embryonic development, its functions in Helicoverpa armigera (H. armigera) and its potential to be used as a target of insecticides remain unclear. We treated H. armigera with HDAC3 siRNA and RGFP966, a specific inhibitor, examining how the HDAC3 loss-of-function affects growth and development. HDAC3 siRNA and RGFP966 treatment increased mortality at each growth stage and altered metamorphosis, hampering pupation and causing abnormal wing development, reduced egg production, and reduced hatching rate. We believe that the misregulation of key hormone-related genes leads to abnormal pupa development in HDAC3 knockout insects. RNA-seq analysis identified 2788 differentially expressed genes (≥two-fold change; p ≤ 0.05) between siHDAC3- and siNC-treated larvae. Krüppel homolog 1 (Kr-h1), was differentially expressed in HDAC3 knockdown larvae. Pathway-enrichment analysis revealed the significant enrichment of genes involved in the Hippo, MAPK, and Wnt signaling pathways following HDAC3 knockdown. Histone H3K9 acetylation was increased in H. armigera after siHDAC3 treatment. In conclusion, HDAC3 knockdown dysregulated juvenile hormone (JH)-related and apoptosis-related genes in H. armigera. The results showed that the HDAC3 gene is a potential target for fighting H. armigera. [ABSTRACT FROM AUTHOR]

Background: Epigenetics exerts a vital role in the onset and development of renal cell carcinoma (RCC). Mounting evidence has shed light on the significance of human immune system in response to tumor infiltrating T cells. Hereby, we sought to unmask the immunomodulatory role of histone deacetylase 3 (HDAC3) and its potential upstream molecule, programmed cell death 5 (PDCD5) in RCC. Methods: RCC and adjacent non-cancerous tissues were clinically resected from 58 patients, in which the expression profile of microRNA-195-5p (miR-195-5p), PDCD5, HDAC3, and serum glucocorticoid-inducible kinase 1 (SGK1) was determined by RT-qPCR and Western blot analysis. Their relations were investigated by a series of luciferase assays in combination with ChIP and co-IP. RCC cells (A498) were intervened using gain- and loss-of-function approaches, followed by cell proliferation evaluation. After co-culture with CD3+ T cells, flow cytometry and interferon-γ (IFN-γ) determination were performed. A xenograft tumor mouse model was developed for in vivo validation. Results: PDCD5 was downregulated in RCC tissues and A498 cells. Upregulation of HDAC3, as well as of SGK1, resulted in suppression of A498 cell proliferation and promotion of T cell activation as evidenced by higher IFN-γ expression. Re-expression of PDCD5 downregulated HDAC3, causing a subsequent upregulation of miR-195-5p, while miR-195-5p could inversely modulate its target gene, SGK1. The regulatory mechanism appeared to be functional in vivo. Conclusion: Our results highlight the possible manipulation by PDCD5 on RCC cell proliferation and T cell activation, which provides new clues to better understand the immune balance in RCC progression. [ABSTRACT FROM AUTHOR]

Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in Kras mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell-intrinsic transcriptional regulator of the tumor immune microenvironment. In Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10 . Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse Kras , LKB1 (KL) and Kras , p53 (KP) mutant lung cancer cells through an NF-κB/p65-dependent mechanism. Using genetically engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors and resulted in enhanced T cell recruitment at least in part via Cxcl10 . Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 expression from that of immunosuppressive chemokines and that combination treatment of entinostat with trametinib enhanced T cell recruitment into lung tumors in vivo. Finally, we showed that T cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T cell recruitment into Kras mutant lung tumors., Competing Interests: Competing interests statement:The authors declare no competing interest.

Proliferative vitreoretinopathy(PVR) is a type of fibrotic eye disease with a poor clinical prognosis. Increasing evidence has shown that the primary pathological mechanism of PVR is the epithelial-mesenchymal transition(EMT) of retinal pigment epithelium(RPE) cells. Histone deacetylase 3(HDAC3) is a crucial enzyme involved in regulating the acetylation level of proteins. Several studies have reported associations between HDAC3 levels and EMT in various tumors; however, the specific effect of HDAC3 on PVR remains largely unknown. The current study found that HDAC3 was highly expressed in both human PVR membranes and experimental PVR. In vivo, silencing HDAC3 in RPE cells reduced their ability to develop experimental PVR through suppression of EMT. In vitro, inhibition of HDAC3 in RPE cells suppressed EGF-mediated cell proliferation, migration, and EMT. Additionally, overexpression of HDAC3 in RPE cells promoted cell proliferation, migration, and EMT. Mechanistically, the results of chromatin immunoprecipitation(ChIP) and luciferase assays revealed a direct binding of the transcription factor MAZ to the promoter region of HDAC3, thereby promoting its transcription. Furthermore, It was demonstrated that HDAC3 facilitated EMT by interacting with AKT and contributing to its deacetylation. In summary, our findings indicated the involvement of HDAC3 in the EMT of RPE cells, as well as its role in PVR through the regulation of the AKT pathway. These results suggested that targeting HDAC3 could be a potential strategy for preventing and treating PVR., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)

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. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum histone Deacetylase 3(HDAC3), High Mobility Group B 1(HMGB-1) and the occurrence, development and structural remodeling of nonvalvular atrial fibrillation. Methods: Patients admitted to non-valvular atrial fibrillation (atrial fibrillation AF group, n=166) were selected and divided into paroxysmal atrial fibrillation group (paroxysmal AF group, n=42), persistent atrial fibrillation group (persistent AF group, n=63), and permanent atrial fibrillation group (permanent AF group, n=61).50 cases of sinus rhythm were selected as the control group, general clinical data, heart color ultrasound, NT-proBNP, and the levels of HDAC 3 and HMGB-1 were determined by enzyme-linked adsorption immunoassay (ELISA). Results: The levels of HDAC3, HMGB-1, LAD, and LVEDD were all higher than those in the control group (P <0.05); The levels of LAD, LVEDD, HDAC3, and HMGB-1 were all higher in the permanent AF groups than in the persistent AF versus paroxysmal AF groups (P <0.05), And the persistent AF group was higher than the paroxysmal AF group (P <0.05); According to the Pearson correlation analysis, HDAC3 vs. LAD (r=0.635), P<0.01), LVEDD(r=0.651, P<0.01), HMGB-1(r=0.757, P <0.01) showed a positive correlation; HMGB-1 was compared with LAD (r=0.658), P<0.01), LVEDD(r=0.569, P <0.01) showed a positive correlation; After a binary logistic regression analysis, HDAC3(OR= 1.712, 95%CI:1.070-2.739, P<0.05), HMGB-1(OR=1.287, 95%CI:1.008-1.634, P <0.05) was associated with whether atrial fibrillation occurred. Conclusion: The levels of HDAC3 and HMGB-1 are correlated to the occurrence and development of AF and are independent risk factors for the occurrence of AF; HDAC3 and HMGB-1 levels are related to the structural remodeling of atrial fibrillation. [ABSTRACT FROM AUTHOR]

Dysfunctional histone deacetylases (HDACs) elicit unrestrained fibrosis and damage to organs. With regard to the link between HDACs and fibrosis, this research is practiced to decipher the concrete mechanism of HDAC3 in hyperuricemia (HN)-induced renal interstitial fibrosis (RIF) from microRNA-19b-3p/splicing factor 3b subunit 3 (miR-19b-3p/SF3B3) axis. The HN model was established on rats to induce RIF by oral administration of adenine and potassium oxalate. HN rats were injected with miR-19b-3p- or HDAC3-related vectors to figure out their effects on RIF through detecting 24-h urine protein, uric acid (UA), blood urea nitrogen (BUN) and serum creatinine (Scr) contents and α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and fibronectin (FN) contents in renal tissues and observing pathological damages and RIF index of renal tissues. HDAC3, miR-19b-3p and SF3B3 expression in renal tissues were tested, along with their interactions. Elevated HDAC3 and SF3B3 and reduced miR-19b-3p were displayed in renal tissues of HN rats. Suppressed HDAC3 or promoted miR-19b-3p relieved HN-induced RIF, as reflected by their inhibitory effects on 24 h urine protein, UA, BUN, Scr, α-SMA, TGF-β1, and FN contents and RIF index and their ameliorated effects on pathological damages of renal tissues. HDAC3 bound to the promoter of miR-19b-3p to regulate SF3B3. MiR-19b-3p depletion abrogated down-regulated HDAC3-induced effects on HN-induced RIF. It is delineated that depressed HDAC3 relives HN-induced RIF through restoring miR-19b-3p and knocking down SF3B3, replenishing the references for RIF curing. [ABSTRACT FROM AUTHOR]

Abstract Background The mechanism of histone deacetylase 3 (HDAC3) in colorectal cancer (CRC) has already been discussed. However, the feedback loop of HDAC3/microRNA (miR)-296-3p and transforming growth factor β-induced factor 1 (TGIF1) in CRC has not been explained clearly. Thus, the mainstay of this study is to delve out the mechanism of this axis in CRC. Methods To demonstrate that HDAC3 regulates the miR-296-3p/TGIF1/TGFβ axis and is involved in CRC progression, a series of cell biological, molecular and biochemical approaches were conducted from the clinical research level, in vitro experiments and in vivo experiments. These methods included RT-qPCR, Western blot assay, cell transfection, MTT assay, EdU assay, flow cytometry, scratch test, Transwell assay, dual luciferase reporter gene assay, chromatin immunoprecipitation, nude mouse xenograft, H&E staining and TUNEL staining. Results Higher HDAC3 and TGIF1 and lower miR-296-3p expression levels were found in CRC tissues. HDAC3 was negatively connected with miR-296-3p while positively correlated with TGIF1, and miR-296-3p was negatively connected with TGIF1. Depleted HDAC3 elevated miR-296-3p expression and reduced TGIF1 expression, decreased TGFβ pathway-related proteins, inhibited CRC proliferation, invasion, and migration in vitro and slowed down tumor growth and induction of apoptosis in vivo, which were reversed by miR-296-3p knockdown. Restored miR-296-3p suppressed TGIF1 and reduced TGFβ pathway-related proteins, inhibited CRC proliferation, invasion, and migration in vitro and slowed down tumor growth and induction of apoptosis in vivo, which were reversed by TGIF1 overexpression. Conclusion This study illustrates that down-regulation of HDAC3 or TGIF1 or up-regulation of miR-296-3p discourages CRC cell progression and slows down tumor growth, which guides towards a novel direction of CRC treatment.

Abstract Background The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances. Histone deacetylase 3 (Hdac3) has been reported to be a crucial regulator in alveologenesis. Hence, this study aims to investigate the mechanism of Hdac3 in the abnormal pulmonary angiogenesis and alveolarization of BPD. Methods A hyperoxia-induced BPD model of was developed in newborn mice, and primary lung fibroblasts were isolated from adult mice. Hdac3 was knocked out in vivo and knocked down in vitro, while microRNA (miR)-17 was downregulated in vivo and in vitro to clarify their roles in abnormal pulmonary angiogenesis and alveolarization. Mechanistic investigations were performed on the interplay of Hdac3, miR-17-92 cluster, enhancer of zeste homolog 1 (EZH1), p65 and placental growth factor (Pgf). Results Hdac3 was involved in abnormal alveolarization and angiogenesis in BPD mice. Further, the expression of the miR-17-92 cluster in BPD mice was downregulated by Hdac3. miR-17 was found to target EZH1, and Hdac3 rescued the inhibited EZH1 expression by miR-17 in lung fibroblasts. Additionally, EZH1 augmented Pgf expression by recruiting p65 thus enhancing the progression of BPD. Hdac3 augmented the recruitment of p65 in the Pgf promoter region through the miR-17/EZH1 axis, thus enhancing the transcription and expression of Pgf, which elicited abnormal angiogenesis and alveolarization of BPD mice. Conclusions Altogether, the present study revealed that Hdac3 activated the EZH1-p65-Pgf axis through inhibiting miR-17 in the miR-17-92 cluster, leading to accelerated abnormal pulmonary angiogenesis and alveolarization of BPD mice.

Objective To investigate the molecular mechanism of hypoxia-decreased NO secretion in vascular endothelial cells, and to explore the intervention role of butyrate (Bur) in the process. Methods Human umbilical vein endothelial cells (HUVECs) were divided into normoxia group (21% O2), hypoxia group (1% O2), hypoxia plus solvent control group, hypoxia plus Bur group (4 mmol/L Bur), hypoxia plus control siRNA group, and hypoxia plus HDAC3 siRNA group. The NO content in the supernatant was tested by NO Assay Kit. The mRNA expression of endothelial nitric oxide synthetase (eNOS) was detected by RT-PCR, and its protein level and that of histone deacetylase 3 (HDAC3) were measured by Western blotting. The interaction of HDAC3 to eNOS was analyzed by co-immunoprecipitation. Results Compared with the normoxia group, hypoxia for 6 h resulted in significant decrease in the NO level in the supernatant (P < 0.05), and reduced eNOS protein level though no change in its mRNA level. In the hypoxic HUVECs, HDAC3 protein level did not changed when compared with the normoxia group. Co-immunoprecipitation analysis showed that hypoxia induced the interaction of HDAC3 with eNOS, and suppressed the acetylation of eNOS protein. The level of eNOS protein was obviously increased in the hypoxia plus HDAC3 siRNA group than the hypoxia plus control siRNA group. Compared with the hypoxia plus solvent control group, the level of NO secretion and eNOS protein were increased significantly in hypoxia plus Bur group (both P < 0.05), but the interaction between the HDAC3 and eNOS was decreased and acetylation of eNOS protein was increased. Conclusion Hypoxia induces HDAC3-eNOS binding and inhibits acetylation of eNOS protein, which might be due to its destruction in eNOS stability and suppression in NO secretion. While, Bur treatment can reverse above process in vascular endothelial cells.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by progressive and irreversible lung scarring associated with persistent activation of fibroblasts. Epigenetics could integrate diverse microenvironmental signals, such as stiffness, to direct persistent fibroblast activation. Histone modifications by deacetylases (HDAC) may play an essential role in the gene expression changes involved in the pathological remodeling of the lung. Particularly, HDAC3 is crucial for maintaining chromatin and regulating gene expression, but little is known about its role in IPF. In the study, control and IPF-derived fibroblasts were used to determine the influence of HDAC3 on chromatin remodeling and gene expression associated with IPF signature. Additionally, the cells were grown on hydrogels to mimic the stiffness of a fibrotic lung. Our results showed a decreased HDAC3 in the nucleus of IPF fibroblasts, which correlates with changes in nucleus size and heterochromatin loss. The inhibition of HDAC3 with a pharmacological inhibitor causes hyperacetylation of H3K9 and provokes an increased expression of Col1A1, ACTA2, and p21. Comparable results were found in hydrogels, where matrix stiffness promotes the loss of nuclear HDAC3 and increases the profibrotic signature. Finally, latrunculin b was used to confirm that changes by stiffness depend on the mechanotransduction signals. Together, these results suggest that HDAC3 could be a link between epigenetic mechanisms and the fibrotic microenvironment.

Acute lung injury (ALI) and its severe counterpart, acute respiratory distress syndrome (ARDS), are critical respiratory conditions with high mortality rates due primarily to acute and intense pulmonary inflammation. Despite significant research advances, effective pharmacological treatments for ALI and ARDS remain unavailable, highlighting an urgent need for therapeutic innovation. Notably, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the irreversible progression of fibrosis, which is initiated by repeated damage to the alveolar epithelium and leads to excessive extracellular matrix deposition. This condition is further complicated by dysregulated tissue repair and fibroblast dysfunction, exacerbating tissue remodeling processes and promoting progression to terminal pulmonary fibrosis. Similar to that noted for ALI and ARDS, treatment options for IPF are currently limited, with no specific drug therapy providing a cure. Histone deacetylase 3 (HDAC3), a notable member of the HDAC family with four splice variants (HD3α, -β, -γ, and -δ), plays multiple roles. HDAC3 regulates gene transcription through histone acetylation and adjusts nonhistone proteins posttranslationally, affecting certain mitochondrial and cytoplasmic proteins. Given its unique structure, HDAC3 impacts various physiological processes, such as inflammation, apoptosis, mitochondrial homeostasis, and macrophage polarization. This article explores the intricate role of HDAC3 in ALI/ARDS and IPF and evaluates its therapeutic potential the treatment of these severe pulmonary conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Liu, Wang and Gu.)

Background: Sepsis-induced acute lung injury (ALI) leads to severe hypoxemia and respiratory failure, contributing to poor prognosis in septic patients. Endotoxin dissemination triggers oxidative stress and the release of inflammatory cytokines in macrophages, initiating diffuse alveolar damage. The role of epigenetic histone modifications in organ injury is increasingly recognized. The present study aimed to investigate the use of a histone modification inhibitor to alleviate sepsis-induced ALI, revealing a new strategy for improving sepsis patient survival., Methods: In vivo models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated in vitro by stimulating Tamm-Horsfall protein-1 (THP-1) cells with lipopolysaccharide. Hematoxylin and eosin staining, blood gas analysis and pulmonary function tests were utilized to assess the extent of lung tissue damage. Western blot analysis, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence were used to measure the levels and distribution of the indicated indicators within cells and tissues. Reactive oxygen species and autophagic flux alterations were detected using specific probes., Results: BRD3308, which is a inhibitor of histone deacetylase 3, improved lung tissue damage, inflammatory infiltration and edema in ALI by inhibiting Nod-like receptor protein3-mediated pyroptosis in macrophages. By upregulating autophagy, BRD3308 improved the disruption of redox balance in macrophages and reduced the accumulation of reactive oxygen species. Mechanistically, BRD3308 inhibited histone deacetylase 3 activity by binding to it and altering its conformation. Following histone deacetylase 3 inhibition, acetylation of H3K27 was significantly increased. Moreover, the increase in H3K27Ac led to the upregulation of autophagy-related gene 5, a key component of autophagosomes, thereby activating autophagy., Conclusions: BRD3308 inhibits oxidative stress and pyroptosis in macrophages by modulating histone acetylation, thereby preventing sepsis-induced ALI. The present study provides a potential strategy and theoretical basis for the clinical treatment of sepsis-induced ALI., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Objectives: It is unclear whether parental consumption of non-nutritive sweetener (NNS) can affect subsequent generations. The aim of this study was to determine whether chronic parental consumption of sucralose and stevia in mice affects body weight gain and liver and intestinal expression of histone deacetylase 3 (Hdac3) in these animals and in the subsequent first filial (F1) and second filial (F2) generations., Methods: Male and female mice (n = 47) were divided into three groups to receive water alone or supplemented with sucralose (0.1 mg/mL) or stevia (0.1 mg/mL) for 16 wk (parental [F0] generation). F0 mice were bred to produce the F1 generation; then, F1 mice were bred to produce the F2 generation. F1 and F2 animals did not receive NNSs. After euthanasia, hepatic and intestinal expression of Hdac3 was determined by quantitative reverse transcription polymerase chain reaction., Results: Body weight gain did not differ between the three groups in the F0 generation, but it was greater in the F1 sucralose and stevia groups than in the control group. Consumption of both NNSs in the F0 generation was associated with lower Hdac3 expression in the liver and higher in the intestine. Hepatic Hdac3 expression was normalized to the control values in the F1 and F2 animals of the sucralose and stevia groups. Intestinal expression was still higher in the F1 generations of the sucralose and stevia groups but was partially normalized in the F2 generation of these groups, compared with control., Conclusions: NNS consumption differentially affects hepatic and intestinal Hdac3 expression. Changes in hepatic expression are not transmitted to the F1 and F2 generations whereas those in intestinal expression are enhanced in the F1 and attenuated in the F2 generations., 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 Inc. All rights reserved.)

Our study aims to identify the impact of histone deacetylase 3 (HDAC3) and microRNA-376c-3p (miR-376c-3p) on gastric cancer (GC) by targeting wingless-type MMTV integration site family member 2b (WNT2b). Levels of miR-376c-3p, HDAC3 and WNT2b were assessed. GC cells were treated with altered HDAC3 or miR-376c-3p to evaluate their biological functions, and rescue experiment was performed to assess the effect of WNT2b on GC cells. The tumor growth in vivo was observed. HDAC3 and WNT2b were up-regulated while miR-376c-3p was reduced in GC tissues and cell lines. The inhibited HDAC3 or elevated miR-376c-3p could restrain malignant behaviors of GC cells in vitro , and also suppress the xenograft growth. WNT2b silencing reduced the effect of miR-376c-3p inhibition while WNT2b overexpression mitigated that of miR-376c-3p promotion on GC cell growth. Inhibiting HDAC3 promotes miR-376c-3p to suppress malignant phenotypes of GC cells via reducing WNT2b, thereby restricting GC development. • HDAC3 and WNT2b are elevated while miR-376c-3p is reduced in GC tissues. • Inhibited HDAC3/elevated miR-376c-3p suppress WNT2b expression in GC cells. • Inhibited HDAC3/elevated miR-376c-3p reduce GC cell growth. • Inhibited HDAC3/elevated miR-376c-3p accelerate GC cell apoptosis. • WNT2b is a direct target gene of miR-376c-3p. [ABSTRACT FROM AUTHOR]

Increased histone deacetylase 3 (HDAC3) has been demonstrated to contribute to the pathogenesis of myocardial ischemia-reperfusion injury (MI/RI). Therefore, the goal of this study was to investigate how HDAC3 regulated MI/RI by mediating microRNA (miR)-494-3p/dromodomain-containing protein 4 (BRD4) axis. The MI/RI model was established by ligating the right anterior descending coronary artery. Cardiomyocytes from newborn mice were treated with hypoxia/reoxygenation (H/R). Gain-of-function and loss-of-function approaches were implemented to figure out the roles of miR-494-3p and HDAC3 in MI/RI. miR-494-3p, HDAC3, and BRD4 in myocardial tissues of mice with MI/RI and H/R-treated cardiomyocytes were detected. The relationships between miR-494-3p and HDAC3 and BRD4 were identified. Reduced miR-494-3p and upregulated HDAC3 and BRD4 exhibited in myocardial tissues of mice with MI/RI and H/R-treated cardiomyocytes. Inhibited HDAC3 or elevated miR-494-3p repressed the inflammation and apoptosis, improved cardiac function, and ameliorated myocardial injury in myocardial tissues of mice with MI/RI. Suppression of HDAC3 or elevation of miR-494-3p depressed inflammation and apoptosis and promoted cell viability of primary cardiomyocytes. miR-494-3p targeted BRD4. The study concludes that suppressed HDAC3 plays a protective role in MI/RI by upregulation of miR-494-3p and inhibition of BRD4, which could be helpful for MI/RI therapy. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) inhibitors can protect the brain from ischemic injury. This study aimed to identify the regulation of HDAC3 in cerebral ischemic injury. Middle cerebral artery occlusion (MCAO) was performed to establish a mouse model with cerebral ischemic injury, in which expression of HDAC3 and miR-19a was evaluated using RT-qPCR. In MCAO mice with silencing of HDAC3, infarct volume was determined using 2,3,5-triphenyl tetrazolium chloride (TTC) staining, and serum levels of TNF-α, IL-6, and IL-8 were measured using ELISA. An in vitro model was constructed in human umbilical vein endothelial cells (HUVECs) with oxygen-glucose deprivation/reoxygenation (OGD/R), followed by gain- and loss-of-function experiments. Relationships among miR-19a, HDAC3, and syndecan-1 (SDC1) were explored using RIP, ChIP, and dual-luciferase reporter assays. The expression of HDAC3, SDC1, JAK1, and STAT3 along with the extent of JAK1 and STAT3 phosphorylation was measured by Western blot analysis. HUVEC viability, apoptosis, and angiogenesis were assessed by CCK-8, flow cytometry, and angiogenesis assays in vitro separately. We found elevated HDAC3 and downregulated miR-19a expression in the MCAO mice. Decreased TNF-α, IL-6, and IL-8 serum levels were observed in response to silencing of HDAC3. HDAC3 inhibited the expression of miR-19a, which in turn targeted SDC1, leading to JAK1/STAT3 signaling pathway activation. HDAC3 overexpression or miR-19a inhibition repressed HUVEC viability and angiogenesis but enhanced HUVEC apoptosis. Our data unraveled the mechanism whereby HDAC3 inhibition ameliorated cerebral ischemic injury by activating the JAK1/STAT3 signaling pathway through miR-19a-mediated SDC1 inhibition. [ABSTRACT FROM AUTHOR]

Objective To investigate the role of histone deacetylase 3 gene (Hdac3) in hematopoiesis by developing a conditional Hdac3 knockout mice. Methods We crossed the Hdac3floxp/floxp mice with Mx1-Cre mice to generate Hdac3fl/flMx1-Cre mice, and then confirmed the mice genotype by PCR. After continuous injection of polyinosinic-polycytidylic acid, Cre was induced to express, and Hdac3fl/flMx1-Cre+ mice (CKO) and Hdac3+/+Mx1-Cre+ mice (WT) were generated. The Hdac3 expression in hematopoietic stem cells (HSCs) was validated by q-PCR. Flow cytometry was used to detect the number and proportion of lymphocytes and the frequencies of CD3+ cells and B220+ cells in the peripheral blood (PB). Hematoxylin and eosin staining (HE) was applied to observe the morphology of the thymus and spleen. In vitro colony-forming assay was conducted to determine differentiation capacity of the hematopoietic stem/progenitor (LSK) cells. Results The CKO mouse model was successfully constructed. Flow cytometry analysis of the peripheral blood showed a significant decreased number (P < 0.001) and percentage (P < 0.01) of the lymphocytes in the CKO mice as compared with the WT mice. Subpopulation analysis of the lymphocytes showed that the percentages of CD3+ lymphocytes (P < 0.01) and B220+ lymphocytes (P < 0.001) were significantly decreased in PB of CKO mice than of WT mice, while an obviously elevated frenquency of CD11b+ myeloid cells was found in PB of CKO mice (P < 0.01). HE staining showed the decrease of lymphogenesis in the thymus and spleen of CKO mice. The in vitro colony-forming assay showed Hdac3-deficient HSCs had deletion in the pre-B colony-forming units, but did not affect colony-forming units of myeloid precursors. Conclusion Hdac3 promotes the lymphogenesis of the HSCs in mice.

Atherosclerosis (AS) is one of the leading causes of cardiovascular diseases. Studies have revealed critical roles of microRNAs (miRNAs) in the progression of AS. This study was conducted to elucidate the role and mechanism by which miR-19b influences AS. Human umbilical vein endothelial cells (HUVECs) were treated with oxidized-low-density lipoprotein (ox-LDL), and an AS mouse model was generated with the help of ApoE −/− mice using a high-fat diet regimen. The expression patterns of peroxisome proliferator-activated receptor γ (PPARγ), nuclear factor κB (NF-κB)/p65, miR-19b and histone deacetylase 3 (HDAC3) were then characterized by reverse transcription quantitative polymerase chain reaction and Western blot analysis. In addition, the relationship among PPARγ, NF-κB/p65, miR-19b and HDAC3 was evaluated by co-immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter gene assays. Gain- and loss-of-function experiments were also performed to examine their functional significance on ox-LDL-induced inflammation in HUVECs. Enzyme-linked immunosorbent assay was applied to determine the expression patterns of inflammatory factors in AS mice. PPARγ and HDAC3 were poorly expressed, while miR-19b and NF-κB/p65 were highly expressed in ox-LDL-induced HUVECs and arterial tissues of AS mice. PPARγ inhibited ox-LDL-induced inflammation in HUVECs by ubiquitination and degradation of NF-κB/p65. miR-19b, downregulated by HDAC3, targeted PPARγ and negatively-regulated its expression. Upregulated PPARγ or HDAC3 or downregulated miR-19b or NF-κB/p65 reduced TNF-α and IL-1β expression levels in ox-LDL-induced HUVECs and AS mice. Collectively, the results show that HDAC3 upregulation prevents inflammation to inhibit AS by inactivating NF-κB/p65 via upregulation of miR-19b-mediated PPARγ, providing a basic therapeutic consideration for AS treatment. [Display omitted] • PPARγ inhibits NF-κB/p65 expression and ox-LDL-induced EC inflammation. • miR-19b inhibits PPARγ to promote atherosclerosis inflammation. • miR-19b represses ox-LDL-induced inflammation in ECs by targeting PPARγ. • HDAC3 suppresses miR-19b and NF-κB/p65 pathway and activates PPARγ to inhibit inflammation. • This study provides a new idea for the mechanism of atherosclerotic inflammation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Long‐term high‐concentrate (HC) diet feeding increased bacterial endotoxins, which translocated into the mammary glands of dairy goats and induced inflammatory response. γ‐d‐Glutamyl‐meso‐diaminopimelic acid (iE‐DAP), bacterial peptidoglycan component, triggered inflammatory response through activating nucleotide oligomerization domain protein 1 (NOD1) signaling pathway. While dietary supplemented with sodium butyrate (SB) relieved inflammatory response and improved animal health and production. To investigate the effects and the mechanisms of action of SB on the inflammatory response in the mammary glands of dairy goats fed HC diet, 12 Saanen dairy goats were randomly assigned into HC group and SB regulated (BHC) group. RESULTS: The results showed that SB supplementation attenuated ruminal pH decrease caused by HC diet in dairy goats resulting in a decrease of proinflammatory cytokines and iE‐DAP plasma concentration and the mRNA expression of NOD1 and other inflammation‐related genes. The protein levels of NOD1, NF‐κB p65 and NF‐κB pp65 were decreased by the SB supplementation. The expression of histone deacetylase 3 (HDAC3) was also inhibited by the SB supplementation. Meanwhile, the chromatin compaction ratios and DNA methylation levels of NOD1 and receptor‐interacting protein 2 (RIP2) of BHC group were upregulated. CONCLUSION: Collectively, the SB supplementation mitigated the inflammatory response in the mammary glands of dairy goats during HC‐induced subacute ruminal acidosis (SARA) by inhibiting the activation of the NOD1/NF‐κB signaling pathway through the decrease of the iE‐DAP concentration in the rumen fluid and plasma and HDAC3 expression. DNA methylation and chromatin remodeling also contributed to the anti‐inflammatory effect of SB. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Background: Oxidative stress (OS) and inflammatory reactions play pivotal roles in secondary brain injury after traumatic brain injury (TBI). Histone deacetylase 3 (HDAC3) controls the acetylation of histones and non-histones, which has a significant impact on the central nervous system's reaction to damage. This research determined the implications of RGFP966, a new and specific inhibitor of HDAC3, for the antioxidant (AO) systems mediated by nuclear factor erythroid2-related factor 2 (Nrf2) and the Nod-like receptor protein 3 (NLRP3) inflammasome in TBI. The study also studied the underlying mechanisms of RGFP966's actions. Our objective was to examine the impacts and underlying RGFP966 mechanisms in TBI., Methods: In vitro , a rat cortical neuron OS model was induced by H 2 O 2 , followed by the addition of RGFP966 to the culture medium. Neurons were collected after 24 h for western blot (WB), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 2'-7'-dichlorodihydrofluorescein diacetate staining. In vivo , RGFP966 (10 mg/kg) was administered post-TBI. Brain tissue water content and modified neurological severity scores were assessed 72 h post-injury. Cortical tissues surrounding the focal injury were subjected to western blot, TUNEL staining, Nissl staining and immunofluorescence/immunohistochemistry staining, and malondialdehyde level, hindered glutathione content and superoxide dismutase activity were measured. Serum was collected for the enzyme-linked immunosorbent assay. Nrf2-specific shRNA lentivirus was injected into the lateral ventricle of rats for 7 days, and cerebral cortex tissue was analyzed by WB and real-time polymerase chain reaction., Results: During in vitro and in vivo experiments, RGFP966 suppressed HDAC3 expression, promoted Nrf2 nuclear translocation, activated downstream AO enzymes, mitigated excessive reactive oxygen species production and alleviated nerve cell apoptosis. RGFP966 effectively reduced brain edema and histological damage and enhanced neurological and cognitive function in rats with TBI. RGFP966 markedly inhibited NLRP3 inflammasome activation mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4). Nrf2 knockdown in TBI rats attenuated the AO and anti-inflammatory, neuroprotective impacts of RGFP966., Conclusions: Overall, our findings demonstrate that RGFP966 can mitigate the first brain damage and neurological impairments in TBI. The underlying mechanism involves triggering the Nrf2-mediated AO system and negatively regulating the HMGB1/TLR4-mediated NLRP3 inflammasome pathway., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Histone deacetylase (HDAC) has been implicated in rheumatoid arthritis (RA) progression. We investigated the roles of histone deacetylase 3 (HDAC3) involved in RA-associated interstitial lung disease (ILD) fibrosis. Firstly, we measured the expression of HDAC3 and interleukin 17 receptor A (IL17RA) in lung tissue samples from normal controls, idiopathic pulmonary fibrosis (IPF) patients, and RA-ILD patients. Next, chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were employed to detect the interaction between HDAC3 and microRNA-19a-3p (miR-19a-3p) and between miR-19a-3p and IL17RA. Further, immunohistochemistry was used to localize HDAC3 and IL17RA expression in lung tissues. Additionally, functional assays were conducted followed by expression determination of HDAC3, miR-19a-3p, and IL17RA with reverse transcription quantitative PCR (RT-qPCR) and Western blot analysis. The effect of HDAC3 on RA-ILD in the constructed RA-ILD mouse model was also studied based on arthritis assessment. We found overexpressed HDAC3 and IL17RA as well as silenced miR-19a-3p in RA-ILD mouse model and RA-ILD patients. In the mouse model, HDAC3 downregulated miR-19a-3p in lung fibroblasts to promote the progression of RA-ILD fibrosis. In lung fibroblasts of RA-ILD mice, IL17RA was a target gene of miR-19a-3p. miR-19a-3p negatively regulated IL17RA, thereby increasing the expression of fibrosis markers, COL1A1, COL3A1, and FN, in lung fibroblasts of mice. Taken together, HDAC3 upregulated IL17RA expression by targeting miR-19a-3p to facilitate the RA-ILD fibrosis development, which sheds light on a new HDAC3/miR-19a-3p/IL17RA axis functioning in RA-ILD fibrosis.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic beta-cells. Multiple microRNAs (miRNAs) have been implicated in T1DM pathogenesis. Although histone deacetylase 3 (HDAC3) has been reported to be involved in T1DM, the underlying mechanisms remain to be further elucidated. This study was designed to investigate the potential regulatory role of Hdac3 on T1DM progression. The expression of miR-296-5p and B-cell leukemia-XL (BCL-XL) was determined using RT-qPCR and Western blot assay in peripheral blood mononuclear cells (PBMCs) of patients with T1DM, tumor necrosis factor-α (TNF-α)- and cycloheximide (CHX)-induced cell model, and streptozotocin (STZ)-induced rat model. The binding affinity between miR-296-5p and Bcl-xl was verified by using dual-luciferase reporter gene assay, and the binding between Hdac3 and the promoter region of miR-296-5p was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. miR-296-5p expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between miR-296-5p and Bcl-xl in mouse TE15 B lymphocytes. Bcl-xl was further validated to be targeted and negatively regulated by miR-296-5p in 293 T cells. Hdac3 inhibited miR-296-5p expression by binding to its promoter region. The effects of overexpressed Hdac3 on lymphocyte apoptosis was counterweighed via downregulation of Bcl-xl or upregulation of miR-296-5p, the mechanism of which was further validated in a rat model of DM. Taken together, the Hdac3-mediated upregulation of Bcl-xl via inhibiting miR-296-5p promoter activity enhanced the anti-apoptotic capacity of lymphocytes to accelerate the occurrence of T1DM.

Progressive accumulation of amyloid-β (Aβ) plaques in the brain is a characteristic pathological change in Alzheimer’s disease (AD). We previously found the expression of lipoprotein lipase (LPL) was increased in SH-SY5Y cells exposed to low-dose Aβ and decreased in cells with high-dose Aβ exposure, but the molecular mechanism is still unclear. Based on previous studies, the opposite regulation of histone deacetylase2 (HDAC2) and HDAC3 on LPL expression probably explain the above molecular mechanism, in which microRNA-29a and peroxisome proliferator-activated receptor γ (PPARγ) may be involved. This study further revealed the mechanism of HDAC2 and HDAC3 on conversely regulating LPL expression. The results showed that HDAC2 down-regulated microRNA-29a by decreasing histone acetylation (Ace-H3K9) level in its promoter region, subsequently increasing LPL expression directly or through PPARγ/LPL pathway; HDAC3 decreased LPL expression through inhibiting Ace-H3K9 levels in LPL and PPARγ promoter regions and up-regulating microRNA-29a. This study also found that with increasing concentrations of Aβ in cells, HDAC2 and HDAC3 expression were gradually increased, and Ace-H3K9 levels in LPL and PPARγ promoter region regulated by HDAC3 were decreased correspondingly, while Ace-H3K9 levels in microRNA-29a promoter region modulated by HDAC2 were not decreased gradually but presented a U-shaped trend. These may lead to the results that a U-shaped alteration in microRNA-29a expression, subsequently leading to an inverse U-shaped alteration in PPARγ or LPL expression. In conclusion, HDAC2 and HDAC3 at least partly mediate LPL expression variations in different concentrations of Aβ exposed SH-SY5Y cells, in which microRNA-29a and PPARγ are involved, and the histone acetylation level in microRNA-29a promoter region plays a key role.

Histone deacetylase 3 (HDAC3) is a potential target for the treatment of human diseases such as cancers, diabetes, chronic inflammation and neurodegenerative diseases. Previously, we proposed a virtual screening (VS) pipeline named “Hypo1_FRED_SAHA-3” for the discovery of HDAC3 inhibitors (HDAC3Is) and had thoroughly validated it by theoretical calculations. In this study, we attempted to explore its practical utility in a large-scale VS campaign. To this end, we used the VS pipeline to hierarchically screen the Specs chemical library. In order to facilitate compound cherry-picking, we then developed a knowledge-based pose filter (PF) by using our in-house quantitative structure activity relationship- (QSAR-) modelling approach and coupled it with FRED and Autodock Vina. Afterward, we purchased and tested 11 diverse compounds for their HDAC3 inhibitory activity in vitro. The bioassay has identified compound 2 (Specs ID: AN-979/41971160) as a HDAC3I (IC50 = 6.1 μM), which proved the efficacy of our workflow. As a medicinal chemistry study, we performed a follow-up substructure search and identified two more hit compounds of the same chemical type, i.e. 2–1 (AQ-390/42122119, IC50 = 1.3 μM) and 2–2 (AN-329/43450111, IC50 = 12.5 μM). Based on the chemical structures and activities, we have demonstrated the essential role of the capping group in maintaining the activity for this class of HDAC3Is. In addition, we tested the hit compounds for their in vitro activities on other HDACs, including HDAC1, HDAC2, HDAC8, HDAC4 and HDAC6. We have identified these compounds are HDAC1/2/3 selective inhibitors, of which compound 2 show the best selectivity profile. Taken together, the present study is an experimental validation and an update to our earlier VS strategy. The identified hits could be used as starting structures for the development of highly potent and selective HDAC3Is.

Histone deacetylase (HDAC) has been implicated in rheumatoid arthritis (RA) progression. We investigated the roles of histone deacetylase 3 (HDAC3) involved in RA-associated interstitial lung disease (ILD) fibrosis. Firstly, we measured the expression of HDAC3 and interleukin 17 receptor A (IL17RA) in lung tissue samples from normal controls, idiopathic pulmonary fibrosis (IPF) patients, and RA-ILD patients. Next, chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were employed to detect the interaction between HDAC3 and microRNA-19a-3p (miR-19a-3p) and between miR-19a-3p and IL17RA. Further, immunohistochemistry was used to localize HDAC3 and IL17RA expression in lung tissues. Additionally, functional assays were conducted followed by expression determination of HDAC3, miR-19a-3p, and IL17RA with reverse transcription quantitative PCR (RT-qPCR) and Western blot analysis. The effect of HDAC3 on RA-ILD in the constructed RA-ILD mouse model was also studied based on arthritis assessment. We found overexpressed HDAC3 and IL17RA as well as silenced miR-19a-3p in RA-ILD mouse model and RA-ILD patients. In the mouse model, HDAC3 downregulated miR-19a-3p in lung fibroblasts to promote the progression of RA-ILD fibrosis. In lung fibroblasts of RA-ILD mice, IL17RA was a target gene of miR-19a-3p. miR-19a-3p negatively regulated IL17RA, thereby increasing the expression of fibrosis markers, COL1A1, COL3A1, and FN, in lung fibroblasts of mice. Taken together, HDAC3 upregulated IL17RA expression by targeting miR-19a-3p to facilitate the RA-ILD fibrosis development, which sheds light on a new HDAC3/miR-19a-3p/IL17RA axis functioning in RA-ILD fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Over the years, the roles of microRNAs (miRNAs) and histone deacetylase 3 (HDAC3) in human diseases have been investigated. This study focused on the effect of miR‐19a‐3p and HDAC3 in myocardial ischemia–reperfusion (I/R) injury (MIRI) by targeting cyclin‐dependent kinase 2 (CDK2). Methods: The I/R rat models were established by coronary artery ligation, which were then treated with RGFP966 (an inhibitor of HDAC3), miR‐19a‐3p agomir or antagomir, or silenced CDK2 to explore their roles in the cardiac function, pathological changes of myocardial tissues, myocardial infarction area, inflammatory factors and oxidative stress factors in rats with MIRI. The expression of miR‐19a‐3p, HDAC3, and CDK2 was determined by RT‐qPCR and western blot assay, and the interaction among which was also verified by online prediction, luciferase activity assay and ChIP assay. Results: The results indicated that HDAC3 and CDK2 were upregulated while miR‐19a‐3p was downregulated in myocardial tissues of I/R rats. The inhibited HDAC3/CDK2 or elevated miR‐19a‐3p could promote cardiac function, attenuate pathological changes, inflammatory reaction, oxidative stress, myocardial infarction area and apoptosis of myocardial tissues. HDAC3 mediates miR‐19a‐3p and CDK2 is targeted by miR‐19a‐3p. Conclusion: Inhibited HDAC3 ameliorates MIRI in a rat model by elevating miR‐19a‐3p and reducing CDK2, which may contribute to the treatment of MIRI. [ABSTRACT FROM AUTHOR]

Background: The mechanism of histone deacetylase 3 (HDAC3) in colorectal cancer (CRC) has already been discussed. However, the feedback loop of HDAC3/microRNA (miR)-296-3p and transforming growth factor β-induced factor 1 (TGIF1) in CRC has not been explained clearly. Thus, the mainstay of this study is to delve out the mechanism of this axis in CRC. Methods: To demonstrate that HDAC3 regulates the miR-296-3p/TGIF1/TGFβ axis and is involved in CRC progression, a series of cell biological, molecular and biochemical approaches were conducted from the clinical research level, in vitro experiments and in vivo experiments. These methods included RT-qPCR, Western blot assay, cell transfection, MTT assay, EdU assay, flow cytometry, scratch test, Transwell assay, dual luciferase reporter gene assay, chromatin immunoprecipitation, nude mouse xenograft, H&E staining and TUNEL staining. Results: Higher HDAC3 and TGIF1 and lower miR-296-3p expression levels were found in CRC tissues. HDAC3 was negatively connected with miR-296-3p while positively correlated with TGIF1, and miR-296-3p was negatively connected with TGIF1. Depleted HDAC3 elevated miR-296-3p expression and reduced TGIF1 expression, decreased TGFβ pathway-related proteins, inhibited CRC proliferation, invasion, and migration in vitro and slowed down tumor growth and induction of apoptosis in vivo, which were reversed by miR-296-3p knockdown. Restored miR-296-3p suppressed TGIF1 and reduced TGFβ pathway-related proteins, inhibited CRC proliferation, invasion, and migration in vitro and slowed down tumor growth and induction of apoptosis in vivo, which were reversed by TGIF1 overexpression. Conclusion: This study illustrates that down-regulation of HDAC3 or TGIF1 or up-regulation of miR-296-3p discourages CRC cell progression and slows down tumor growth, which guides towards a novel direction of CRC treatment. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are emerging biomarkers in biological processes and the role of miR‐495‐3p has been identified in melanoma, while the detailed molecular mechanisms remain to be further explored. We aim to explore the effect of histone deacetylase 3 (HDAC3) and miR‐495‐3p on epithelial‐mesenchymal transition (EMT) and oncogenicity of melanoma cells by regulating tumour necrosis factor receptor‐associated factor 5 (TRAF5). Levels of HDAC3, miR‐495‐3p and TRAF5 in melanoma tissues and pigmented nevus tissues were determined, and the predictive roles of HDAC3 and miR‐495‐3p in prognosis of melanoma patients were measured. The melanoma cells were screened and transfected with relative oligonucleotides and plasmids, and the expression of HDAC3, miR‐495‐3p and TRAF5, and phenotypes of melanoma cells were gauged by a series of assays. The relations between HDAC3 and miR‐495‐3p, and between miR‐495‐3p and TRAF5 were confirmed. HDAC3 and TRAF5 were increased while miR‐495‐3p was decreased in melanoma cells and tissues, and the low expression of miR‐495‐3p as well as high expression of HDAC3 indicated a poor prognosis of melanoma patients. Inhibited HDAC3 elevated miR‐495‐3p to suppress EMT and oncogenicity of melanoma cells by reducing TRAF5. HDAC3 particularly bound to miR‐495‐3p and TRAF5 was the target gene of miR‐495‐3p. Our results revealed that down‐regulated HDAC3 elevates miR‐495‐3p to suppress malignant phenotypes of melanoma cells by inhibiting TRAF5, thereby repressing EMT progression of melanoma cells. This study may provide novel targets for melanoma treatment. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic beta-cells. Multiple microRNAs (miRNAs) have been implicated in T1DM pathogenesis. Although histone deacetylase 3 (HDAC3) has been reported to be involved in T1DM, the underlying mechanisms remain to be further elucidated. This study was designed to investigate the potential regulatory role of Hdac3 on T1DM progression. The expression of miR-296-5p and B-cell leukemia-XL (BCL-XL) was determined using RT-qPCR and Western blot assay in peripheral blood mononuclear cells (PBMCs) of patients with T1DM, tumor necrosis factor-α (TNF-α)- and cycloheximide (CHX)-induced cell model, and streptozotocin (STZ)-induced rat model. The binding affinity between miR-296-5p and Bcl-xl was verified by using dual-luciferase reporter gene assay, and the binding between Hdac3 and the promoter region of miR-296-5p was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. miR-296-5p expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between miR-296-5p and Bcl-xl in mouse TE15 B lymphocytes. Bcl-xl was further validated to be targeted and negatively regulated by miR-296-5p in 293 T cells. Hdac3 inhibited miR-296-5p expression by binding to its promoter region. The effects of overexpressed Hdac3 on lymphocyte apoptosis was counterweighed via downregulation of Bcl-xl or upregulation of miR-296-5p , the mechanism of which was further validated in a rat model of DM. Taken together, the Hdac3 -mediated upregulation of Bcl-xl via inhibiting miR-296-5p promoter activity enhanced the anti-apoptotic capacity of lymphocytes to accelerate the occurrence of T1DM. [ABSTRACT FROM AUTHOR]

Disruption of remyelination contributes to neurodegeneration and cognitive impairment in chronically disabled patients. Valproic acid (VPA) inhibits histone deacetylase (HDAC) function and probably promotes oligodendrocyte progenitor cell (OPC) proliferation and differentiation; however, the relevant molecular mechanisms remain unknown. Here, focal demyelinating lesions (FDLs) were generated in mice by two-point stereotactic injection of lysophosphatidylcholine (LPC) into the corpus callosum. Cognitive functions, sensorimotor abilities and histopathological changes were assessed for up to 28 days post-injury with or without VPA treatment. Primary OPCs were harvested and used to study the effect of VPA on OPC differentiation under inflammatory conditions. VPA dose-dependently attenuated learning and memory deficits and robustly protected white matter after FDL induction, as demonstrated by reductions in SMI-32 and increases in myelin basic protein staining. VPA also promoted OPC proliferation and differentiation and increased subsequent remyelination efficiency by day 28 post-FDL induction. VPA treatment did not affect HDAC1, HDAC2 or HDAC8 expression but reduced HDAC3 protein levels. In vitro, VPA improved the survival of mouse OPCs and promoted their differentiation into oligodendrocytes following lipopolysaccharide (LPS) stimulation. LPS caused OPCs to overexpress HDAC3, which translocated from the cytoplasm into the nucleus, where it directly interacted with the nuclear transcription factor PPAR-γ and negatively regulated PPAR-γ expression. VPA decreased the expression of HDAC3 and promoted remyelination and functional neurological recovery after FDL. These findings may support the use of strategies modulating HDAC3-mediated regulation of protein acetylation for the treatment of demyelination-related cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Trinucleotide repeat (TNR) expansions cause nearly 20 severe human neurological diseases which are currently untreatable. For some of these diseases, ongoing somatic expansions accelerate disease progression and may influence age of onset. This new knowledge emphasizes the importance of understanding the protein factors that drive expansions. Recent genetic evidence indicates that the mismatch repair factor MutSβ (Msh2-Msh3 complex) and the histone deacetylase HDAC3 function in the same pathway to drive triplet repeat expansions. Here we tested the hypothesis that HDAC3 deacetylates MutSβ and thereby activates it to drive expansions. The HDAC3-selective inhibitor RGFP966 was used to examine its biological and biochemical consequences in human tissue culture cells. HDAC3 inhibition efficiently suppresses repeat expansion without impeding canonical mismatch repair activity. Five key lysine residues in Msh3 are direct targets of HDAC3 deacetylation. In cells expressing Msh3 in which these lysine residues are mutated to arginine, the inhibitory effect of RGFP966 on expansions is largely bypassed, consistent with the direct deacetylation hypothesis. RGFP966 treatment does not alter MutSβ subunit abundance or complex formation but does partially control its subcellular localization. Deacetylation sites in Msh3 overlap a nuclear localization signal, and we show that localization of MutSβ is partially dependent on HDAC3 activity. Together, these results indicate that MutSβ is a key target of HDAC3 deacetylation and provide insights into an innovative regulatory mechanism for triplet repeat expansions. The results suggest expansion activity may be druggable and support HDAC3-selective inhibition as an attractive therapy in some triplet repeat expansion diseases. [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]