Exclusion of HDAC1/2 complexes by oncogenic nuclear condensates.

Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation.

SARS-CoV-2 NSP5 antagonizes MHC II expression by subverting histone deacetylase 2.

SARS-CoV-2 interferes with antigen presentation by downregulating major histocompatibility complex (MHC) II on antigen-presenting cells, but the mechanism mediating this process is unelucidated. Herein, analysis of protein and gene expression in human antigen-presenting cells reveals that MHC II is downregulated by the SARS-CoV-2 main protease, NSP5. This suppression of MHC II expression occurs via decreased expression of the MHC II regulatory protein CIITA. CIITA downregulation is independent of the proteolytic activity of NSP5, and rather, NSP5 delivers HDAC2 to the transcription factor IRF3 at an IRF-binding site within the CIITA promoter. Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a mechanism by which SARS-CoV-2 limits MHC II expression, thereby delaying or weakening the subsequent adaptive immune response.

Hydroxytyrosol ameliorates stress-induced liver injury through activating autophagy via HDAC1/2 inhibition.

Hydroxytyrosol (HT), a phenolic extra-virgin olive oil compound used as a food supplement, has been recognized to protect liver function and alleviate stress-induced depressive-like behaviors. However, its protective effects against stress-induced liver injury (SLI) remain unknown. Here, the anti-SLI effect of HT was evaluated in mice with chronic unpredictable mild stress-induced SLI. Network pharmacology combined with molecular docking was used to clarify the underlying mechanism of action of HT against SLI, followed by experimental verification. The results showed that accompanying with the alleviation of HT on stress-induced depressive-like behaviors, HT was confirmed to exert the protective effects against SLI, as represented by reduced serum corticosterone (CORT), aspartate aminotransferase and alanine aminotransferase activities, as well as repair of liver structure, inhibition of oxidative homeostasis collapse, and inflammation reaction in the liver. Furthermore, core genes including histone deacetylase 1 and 2 (HDAC1/2), were identified as potential targets of HT in SLI based on bioinformatic screening and simulation. Consistently, HT significantly inhibited HDAC1/2 expression to maintain mitochondrial dysfunction in an autophagy-dependent manner, which was confirmed in a CORT-induced AML-12 cell injury and SLI mice models combined with small molecule inhibitors. We provide the first evidence that HT inhibits HDAC1/2 to induce autophagy in hepatocytes for maintaining mitochondrial dysfunction, thus preventing inflammation and oxidative stress for exerting an anti-SLI effect. This constitutes a novel therapeutic modality to synchronously prevent stress-induced depression-like behaviors and liver injury, supporting the advantaged therapeutic potential of HT.

Hypoxia-activated XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of ΔNp63α expression and promote breast cancer metastasis independent of HIF1α.

Hypoxia is a hallmark of cancer development. However, the molecular mechanisms by which hypoxia promotes tumor metastasis are not fully understood. In this study, we demonstrate that hypoxia promotes breast cancer metastasis through suppression of ΔNp63α in a HIF1α-independent manner. We show that hypoxia-activated XBP1s forms a stable repressor protein complex with HDAC2 and EZH2 to suppress ΔNp63α transcription. Notably, H3K27ac is predominantly occupied on the ΔNp63 promoter under normoxia, while H3K27me3 on the promoter under hypoxia. We show that XBP1s binds to the ΔNp63 promoter to recruit HDAC2 and EZH2 in facilitating the switch of H3K27ac to H3K27me3. Pharmacological inhibition or the knockdown of either HDAC2 or EZH2 leads to increased H3K27ac, accompanied by the reduced H3K27me3 and restoration of ΔNp63α expression suppressed by hypoxia, resulting in inhibition of cell migration. Furthermore, the pharmacological inhibition of IRE1α, but not HIF1α, upregulates ΔNp63α expression in vitro and inhibits tumor metastasis in vivo. Clinical analyses reveal that reduced p63 expression is correlated with the elevated expression of XBP1, HDAC2, or EZH2, and is associated with poor overall survival in human breast cancer patients. Together, these results indicate that hypoxia-activated XBP1s modulates the epigenetic program in suppression of ΔNp63α to promote breast cancer metastasis independent of HIF1α and provides a molecular basis for targeting the XBP1s/HDAC2/EZH2-ΔNp63α axis as a putative strategy in the treatment of breast cancer metastasis.

Epigenetic disruption of histone deacetylase-2 accelerated apoptotic signaling and retarded malignancy in gastric cells.

Background: The objective of this research was to determine whether HDAC2 function is associated with gastric cancer progression. Methods: HDAC2 was knocked out in EPG85.257 cells using CRISPR/Cas9 and tumorigenesis pathways were evaluated. Results: Cell proliferation, colony formation, wound healing and transwell invasion were inhibited in ΔHDAC2:EPG85.257 cells. Quantitative analyses revealed a significant downregulation of MMP1, p53, Bax, MAPK1, MAPK3, pro-Caspase3, ERK1/2, p-ERK1/2, AKT1/2/3, p-AKT1/2/3, p-NF-κB (p65), Twist, Snail and p-FAK transcripts/proteins, while SIRT1, PTEN, p21 and Caspase3 were upregulated in ΔHDAC2:EPG85.257 cells. Conclusion: These results indicated that HDAC2 enhanced migration, colony formation and transmigration ability. HDAC2 inhibition may improve gastric cancer chemotherapy pathways.

DNA changes are the main causes of cancer. Therefore, finding easy ways to manipulate and correct DNA changes has been the biggest medical concern in cancer treatment. Researchers have introduced CRISPR/Cas9 as the newest technology for gene editing that precisely and easily changes the genome of any cell. In our study, histone deacetylase-2 was disrupted in gastric cancer cells using CRISPR technology. This modification reduced growth kinetics and invasion of cancer cells. On the other hand, cell death (also called apoptosis) was induced. Sensitization of the cancer cells to chemotherapeutic agents is noticeable in this research. This study needs to uncover more signaling pathways in vitro and in vivo.

SOX4/HDAC2 Axis Enhances Cell Survivability and Reduces Apoptosis by Activating AKT/MAPK Signaling in Colorectal Cancer.

BACKGROUND: Increased SOX4 (SRY-related HMG-box) activity aids cellular transformation and metastasis. However, its specific functions and downstream targets remain to be completely elusive in colorectal cancer (CRC). AIMS: To investigate the role of SOX4 in CRC progression and the underlying mechanism. METHODS: In the current study, online available datasets of CRC patients were explored to check the expression status of SOX4. To investigate the further functions, SOX4 was overexpressed and knocked down in CRC cells. Colony formation assay, flowcytometry analysis, and MTT assay were used to check for proliferation and apoptosis. Acridine orange staining was done to check the role of SOX4 in autophagy induction. Furthermore, western blot, qRT-PCR, and bioinformatic analysis was done to elucidate the downstream molecular mechanism of SOX4. RESULTS: GEPIA database showed enhanced expression of SOX4 mRNA in CRC tumor, and the human protein atlas (HPA) showed strong staining of SOX4 protein in tumor when compared to the normal tissue. Ectopic expression of SOX4 enhanced colony formation ability as well as rescued cells from apoptosis. SOX4 overexpressed cells showed the formation of acidic vesicular organelles (AVOs) which indicated autophagy. Further results revealed the activation of p-AKT/MAPK molecules upon overexpression of SOX4. SOX4 expression was found to be positively correlated with histone deacetylase 2 (HDAC2). Knockdown of SOX4 or HDAC2 inhibition induced apoptosis, revealed by decrease in BCL2 and increase in BAX expression, and inactivated the p-AKT/MAPK signaling. CONCLUSION: The study uncovers that SOX4/HDAC2 axis improves cell survivability and reduces apoptosis via activation of the p-AKT/MAPK pathway.

USP43 impairs cisplatin sensitivity in epithelial ovarian cancer through HDAC2-dependent regulation of Wnt/ß-catenin signaling pathway.

Epithelial ovarian cancer (EOC) is the leading cause of cancer death all over the world. USP43 functions as a tumor promoter in various malignant cancers. Nevertheless, the biological roles and mechanisms of USP43 in EOC remain unknown. In this study, USP43 was highly expressed in EOC tissues and cells, and high expression of USP43 were associated with a poor prognosis of EOC. USP43 overexpression promoted EOC cell proliferation, enhanced the ability of migration and invasion, decreased cisplatin sensitivity and inhibited apoptosis. Knockdown of USP43 in vitro effectively retarded above malignant progression of EOC. In vivo xenograft tumors, silencing USP43 slowed tumor growth and enhanced cisplatin sensitivity. Mechanistically, USP43 inhibited HDAC2 degradation and enhanced HDAC2 protein stability through its deubiquitylation function. USP43 diminished the sensitivity of EOC cells to cisplatin through activation of the Wnt/ß-catenin signaling pathway mediated by HDAC2. Taken together, the data in this study revealed the functions of USP43 in proliferation, migration, invasion, chemoresistance of EOC cells, and the mechanism of HDAC2-mediated Wnt/ß-catenin signaling pathway. Thus, USP43 might serve as a potential target for the control of ovarian cancer progression.

USP17 regulates preeclampsia by modulating the NF-κB signaling pathway via deubiquitinating HDAC2.

INTRODUCTION: Ubiquitination is a significant post-translational modification engaged in diverse biological processes, such as cell differentiation, metastasis, and protein stability modulation. The dysregulation of ubiquitination and deubiquitination is inextricably linked to disease progression, including preeclampsia (PE). Ubiquitin-specific protease 17 (USP17), a prominent deubiquitinating enzyme that regulates ubiquitination modifications, performs multiple functions at the cellular level, whereas its role in PE remains elusive. In this study, we intended to probe the role of USP17 in PE and its underlying mechanisms. METHODS: The USP17 level in the plasma of PE patients was detected through Elisa. Western blot and qRT-PCR were performed to measure the mRNA and protein level of USP17 in placental tissues. CCK-8, EdU, and transwell assays were conducted to evaluate the proliferation, migration, and invasion of trophoblast cells. The interaction between HDAC2 and USP17 or STAT1 were determined by co-immunoprecipitation and Western blot assays. The expression of NF-κB pathway related proteins was examined using Western blot. RESULTS: USP17 was dramatically downregulated in PE patients. Overexpression of USP17 facilitated trophoblast proliferation, migration, and invasion. Moreover, histone deacetylase 2 (HDAC2) was validated as a substrate of USP17 deubiquitination, and USP17 upregulation enhanced HDAC2 protein level. Furthermore, HDAC2 could interact with and deacetylate Signal transducer and activator of transcription 1 (STAT1), resulting in the enhancement of STAT1 activity and inhibition of NF-κB signaling. DISCUSSION: Our findings disclosed that USP17 augmented the proliferation and invasion of trophoblast by deubiquitinating HDAC2, which will contribute to novel prospective targets for diagnosing and treating PE.

A novel GRK3-HDAC2 regulatory pathway is a key direct link between neuroendocrine differentiation and angiogenesis in prostate cancer progression.

The mechanisms underlying the progression of prostate cancer (PCa) to neuroendocrine prostate cancer (NEPC), an aggressive PCa variant, are largely unclear. Two prominent NEPC phenotypes are elevated NE marker expression and heightened angiogenesis. Identifying the still elusive direct molecular links connecting angiogenesis and neuroendocrine differentiation (NED) is crucial for our understanding and targeting of NEPC. Here we found that histone deacetylase 2 (HDAC2), whose role in NEPC has not been reported, is one of the most upregulated epigenetic regulators in NEPC. HDAC2 promotes both NED and angiogenesis. G protein-coupled receptor kinase 3 (GRK3), also upregulated in NEPC, is a critical promoter for both phenotypes too. Of note, GRK3 phosphorylates HDAC2 at S394, which enhances HDAC2's epigenetic repression of potent anti-angiogenic factor Thrombospondin 1 (TSP1) and master NE-repressor RE1 Silencing Transcription Factor (REST). Intriguingly, REST suppresses angiogenesis while TSP1 suppresses NE marker expression in PCa cells, indicative of their novel functions and their synergy in cross-repressing the two phenotypes. Furthermore, the GRK3-HDAC2 pathway is activated by androgen deprivation therapy and hypoxia, both known to promote NED and angiogenesis in PCa. These results indicate that NED and angiogenesis converge on GRK3-enhanced HDAC2 suppression of REST and TSP1, which constitutes a key missing link between two prominent phenotypes of NEPC.

Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics.

Histone deacetylases are important epigenetic regulators that have been reported to play essential roles in cancer stem cell functions and are promising therapeutic targets in many cancers including glioblastoma. However, the functionally relevant roles of specific histone deacetylases, in the maintenance of key self-renewal and growth characteristics of brain tumour stem cell (BTSC) sub-populations of glioblastoma, remain to be fully resolved. Here, using pharmacological inhibition and genetic loss and gain of function approaches, we identify HDAC2 as the most relevant histone deacetylase for re-organization of chromatin accessibility resulting in maintenance of BTSC growth and self-renewal properties. Furthermore, its specific interaction with the transforming growth factor-ß pathway related proteins, SMAD3 and SKI, is crucial for the maintenance of tumorigenic potential in BTSCs in vitro and in orthotopic xenograft models. Inhibition of HDAC2 activity and disruption of the coordinated mechanisms regulated by the HDAC2-SMAD3-SKI axis are thus promising therapeutic approaches for targeting BTSCs.

Collateral lethality between HDAC1 and HDAC2 exploits cancer-specific NuRD complex vulnerabilities.

Transcriptional co-regulators have been widely pursued as targets for disrupting oncogenic gene regulatory programs. However, many proteins in this target class are universally essential for cell survival, which limits their therapeutic window. Here we unveil a genetic interaction between histone deacetylase 1 (HDAC1) and HDAC2, wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal deletions that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic disruption or dTAG-mediated degradation, we show that targeting HDAC2 suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2-NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders that could leverage HDAC1/2 synthetic lethality to target NuRD vulnerabilities. Altogether, we identify HDAC1/2 collateral synthetic lethality as a potential therapeutic target and reveal an unexplored mechanism for targeting NuRD-associated cancer dependencies.

The HDAC2/YY1/c-Myc signaling axis regulates lung cancer cell migration and proliferation.

Lung cancer is among the most aggressive types of malignant tumors that contributes to cancer-associated deaths worldwide with a high occurrence and fatality rate. Histone deacetylase 2 (HDAC2), prevent the aberrant transcription of a number of genes that are primarily responsible for controlling the cell cycle, cell proliferation, and signaling pathways in numerous cancers. Previous studies reported the role of HDACs and YY1 in the growth and development of several cancers. Although, it is noteworthy that remarkable efforts have been taken for the treatment of lung cancer using molecularly targeted therapies and chemotherapeutic agents, but the outcome is still poor for this critically persistent cancer. Therefore, the aim of the present study is to identify an efficacious, novel therapeutic biomarkers for the successful diagnosis of lung cancer at the early stage of the disease and the molecular insights involved. In the present study, qPCR and western bot data revealed that the expression level of HDAC2 and YY1 were upregulated in the cell lines and tumor samples of lung cancer patients. Moreover, MTT, qPCR, western blot, cell cycle analysis, and migration assays showed that inhibition of HDAC2 reduced YY1 expression, similarly, depletion of YY1 using knockdown approach inhibited the proliferation, migration, invasion, and blockage of the cell cycle by suppressing c-Myc in lung cancer cell lines. In conclusion, the current study findings support the notion that HDAC2's anticancer role was attributed through YY1 regulation by targeting c-Myc and could act as potential novel candidate biomarker for the lung cancer diagnosis.

Mechanism of histone deacetylase HDAC2 in FOXO3-mediated trophoblast pyroptosis in preeclampsia.

Histone deacetylase 2 (HDAC2) has been demonstrated to regulate trophoblast behaviors. However, its role in trophoblast pyroptosis remains unknown. This study sought to analyze the molecular mechanism of HDAC2 in trophoblast pyroptosis in PE. Expression levels of HDAC2, forkhead box O3 (FOXO3), and protein kinase R-like endoplasmic reticulum kinase (PERK) in placenta tissues and HTR8/SVneo cells and H3K27ac levels in cells were determined. Levels of IL-1ß and IL-18 in placenta tissues were determined, and their correlation with HDAC2 was analyzed. Cell proliferation, migration, and invasion were evaluated, and levels of pyroptosis-associated proteins and cytokines were determined. The enrichments of H3K27 acetylation (H3K27ac) and FOXO3 in the FOXO3/PERK promoter region were determined. HDAC2 was downregulated, and FOXO3, PERK, IL-1ß, and IL-18 levels were elevated in PE placenta tissues. In HTR8/SVneo cells, HDAC2 downregulation suppressed cell proliferation, migration, and invasion and increased pyroptosis. HDAC2 erased H3K27ac in the FOXO3 promoter region and repressed FOXO3, and FOXO3 bound to the PERK promoter and increased PERK transcription. Functional rescue experiments revealed that silencing FOXO3 or PERK counteracted HDAC2 downregulation-induced cell pyroptosis. Overall, HDAC2 downregulation enhanced H3K27ac to activate FOXO3 and PERK, leading to the occurrence of trophoblast pyroptosis in PE.

Histone Deacetylase 1 Inhibition by Peptides Containing a DNA Damage-Induced, Nonenzymatic, Histone Covalent Modification.

Treatment of HeLa cells with the DNA damaging agent, bleomycin (BLM), results in the formation of a nonenzymatic 5-methylene-2-pyrrolone histone covalent modification on lysine residues (KMP). KMP is much more electrophilic than other N-acyllysine covalent modifications and post-translational modifications, including N-acetyllysine (KAc). Using histone peptides containing KMP, we show that this modification inhibits the class I histone deacetylase, HDAC1, by reacting with a conserved cysteine (C261) located near the active site. HDAC1 is inhibited by histone peptides whose corresponding N-acetylated sequences are known deacetylation substrates, but not one containing a scrambled sequence. The HDAC1 inhibitor, trichostatin A, competes with covalent modification by the KMP-containing peptides. HDAC1 is also covalently modified by a KMP-containing peptide in a complex milieu. These data indicate that peptides containing KMP are recognized by HDAC1 and are bound in the active site. The effects on HDAC1 indicate that KMP formation in cells may contribute to the biological effects of DNA damaging agents, such as BLM, that form this nonenzymatic covalent modification.

HDAC inhibitor ITF2357 reduces resistance of mutant-KRAS non-small cell lung cancer to pemetrexed through a HDAC2/miR-130a-3p-dependent mechanism.

BACKGROUND: Histone deacetylases (HDAC) contribute to oncogenic program, pointing to their inhibitors as a potential strategy against cancers. We, thus, studied the mechanism of HDAC inhibitor ITF2357 in resistance of mutant (mut)-KRAS non-small cell lung cancer (NSCLC) to pemetrexed (Pem). METHODS: We first determined the expression of NSCLC tumorigenesis-related HDAC2 and Rad51 in NSCLC tissues and cells. Next, we illustrated the effect of ITF2357 on the Pem resistance in wild type-KARS NSCLC cell line H1299, mut-KARS NSCLC cell line A549 and Pem-resistant mut-KARS cell line A549R in vitro and in xenografts of nude mice in vivo. RESULTS: Expression of HDAC2 and Rad51 was upregulated in NSCLC tissues and cells. Accordingly, it was revealed that ITF2357 downregulated HDAC2 expression to diminish the resistance of H1299, A549 and A549R cells to Pem. HDAC2 bound to miR-130a-3p to upregulate its target gene Rad51. The in vitro findings were reproduced in vivo, where ITF2357 inhibited the HDAC2/miR-130a-3p/Rad51 axis to reduce the resistance of mut-KRAS NSCLC to Pem. CONCLUSION: Taken together, HDAC inhibitor ITF2357 restores miR-130a-3p expression by inhibiting HDAC2, thereby repressing Rad51 and ultimately diminishing resistance of mut-KRAS NSCLC to Pem. Our findings suggested HDAC inhibitor ITF2357 as a promising adjuvant strategy to enhance the sensitivity of mut-KRAS NSCLC to Pem.

Human bone marrow mesenchymal stem cell-derived extracellular vesicles reduce inflammation and pyroptosis in acute kidney injury via miR-223-3p/HDAC2/SNRK.

OBJECTIVE: Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) have been demonstrated as a potential therapeutic agent in acute kidney injury (AKI). However, little is known about the mechanisms of action of BMSC-derived EVs in AKI. Based on this, our research was designed to investigate the mechanism behind BMSC-derived EVs controlling inflammation and pyroptosis during AKI. METHODS: Peripheral blood from AKI patients was used for detection of microRNA (miR)-223-3p, HDAC2, and SNRK expression. An AKI rat model was established, and HK-2 cell injury was induced by lipopolysaccharide (LPS) to establish a cellular model. Co-culture with BMSC-derived EVs and/or gain- and loss-of-function assays were conducted in LPS-treated HK-2 to evaluate the functions of BMSCs-EVs, miR-223-3p, HDAC2, and SNRK. AKI rats were simultaneously injected with EVs and short hairpin RNAs targeting SNRK. The interactions among miR-223-3p, HDAC2, and SNRK were evaluated by RIP, ChIP, and dual-luciferase gene reporter assays. RESULTS: Patients with AKI had low miR-223-3p and SNRK expression and high HDAC2 expression in peripheral blood. Mechanistically, miR-223-3p targeted HDAC2 to accelerate SNRK transcription. In LPS-treated HK-2 cells, BMSCs-EVs overexpressing miR-223-3p increased cell viability and diminished cell apoptosis, KIM-1, LDH, IL-1ß, IL-6, TNF-α, NLRP3, ASC, cleaved caspase-1, and IL-18 expression, and GSDMD cleavage, which was nullified by HDAC2 overexpression or SNRK silencing. In AKI rats, BMSCs-EV-shuttled miR-223-3p reduced CRE and BUN levels, apoptosis, inflammation, and pyroptosis, which was abrogated by SNRK silencing. CONCLUSION: Conclusively, BMSC-derived EV-encapsulated miR-223-3p mitigated AKI-induced inflammation and pyroptosis by targeting HDAC2 and promoting SNRK transcription.

MicroRNA-30e-3p reduces coronary microembolism-induced cardiomyocyte pyroptosis and inflammation by sequestering HDAC2 from the SMAD7 promoter.

This study investigates the mechanism by which microRNA (miR)-30e-3p reduces coronary microembolism (CME)-induced cardiomyocyte pyroptosis and inflammation. Cardiac function tests, histological staining, and transmission electron microscopy were performed on CME-model rats injected with adeno-associated viral vectors. Cardiomyocytes were transfected 24 h before a cellular model of pyroptosis was established via treatment with 1 µg/mL lipopolysaccharide (LPS) for 4 h and 5 mM ATP for 30 min. Pyroptosis, inflammation, and Wnt/ß-catenin signaling in cardiomyocytes were detected. Dual-luciferase reporter assays and/or RNA pull-down assays were performed to verify the binding of miR-30e-3p to HDAC2 mRNA or HDAC2 to the SMAD7 promoter. Chromatin immunoprecipitation was used to assess the level of H3K27 acetylation at the SMAD7 promoter. miR-30e-3p and SMAD7 expression levels were downregulated and HDAC2 expression was upregulated with CME. The overexpression of miR-30e-3p restored cardiac functions in CME-model rats and reduced serum cTnI, IL-18, and IL-1ß levels, microinfarcts, inflammatory cell infiltration, apoptosis, collagen content, and GSDMD-N, cleaved caspase-1, and NLRP3 expression in the myocardium, but these effects were reversed by SMAD7 knockdown. The overexpression of miR-30e-3p or knockdown of HDAC2 reduced LDH, IL-18, and IL-1ß secretion, propidium iodide intake, and GSDMD-N, NLRP3, cleaved caspase-1, Wnt3a, Wnt5a, and ß-catenin expression in the cardiomyocyte model. miR-30e-3p inhibited the expression of HDAC2 by binding HDAC2 mRNA. HDAC2 repressed the expression of SMAD7 by catalyzing H3K27 deacetylation at the SMAD7 promoter. miR-30e-3p, by binding HDAC2 to promote SMAD7 expression, reduces CME-induced cardiomyocyte pyroptosis and inflammation.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles carrying miR-655-3p inhibit the development of esophageal cancer by regulating the expression of HIF-1α via a LMO4/HDAC2-dependent mechanism.

OBJECTIVE: This study clarified the function of human umbilical cord mesenchymal stem cell (hUCMSC)-derived extracellular vesicle (EV)-enclosed miR-655-3p in esophageal squamous cell carcinoma (ESCC). METHODS: A Chi-square test and the Kaplan-Meier estimator were used to analyze the prognosis of ESCC in relation to the expression of miR-655-3p. ESCC cells were incubated with PBS or hUCMSC-derived EVs (hUCMSC-EVs) in the conditions of gene modification, after which the malignant behaviors of ESCC cells were assessed and the molecular interactions were determined. The effect of hUCMSC-derived EV-miR-655-3p was also investigated in a nude mouse model of ESCC. RESULTS: Low expression of miR-655-3p indicated poor prognosis of ESCC. hUCMSC-EVs suppressed the malignant behaviors of ESCC cells and the growth and liver metastasis of transplanted tumors. Inhibition of miR-655-3p in hUCMSCs impaired the therapeutic effect of hUCMSC-EVs. LMO4, targeted by miR-655-3p, activated the transcription of HIF-1α by sequestering HDAC2 from HIF-1α promoter. Knockdown of LMO4 suppressed ESCC cell activities, while overexpression of HIF-1α counteracted the tumor suppressive effect of LMO4 knockdown. CONCLUSION: miR-655-3p enclosed in hUCMSC-derived EVs inhibits ESCC progression partially by inactivating HIF-1α via the LMO4/HDAC2 axis.

The epigenetic modifier HDAC2 and the checkpoint kinase ATM determine the responses of microsatellite instable colorectal cancer cells to 5-fluorouracil.

The epigenetic modifier histone deacetylase-2 (HDAC2) is frequently dysregulated in colon cancer cells. Microsatellite instability (MSI), an unfaithful replication of DNA at nucleotide repeats, occurs in about 15% of human colon tumors. MSI promotes a genetic frameshift and consequently a loss of HDAC2 in up to 43% of these tumors. We show that long-term and short-term cultures of colorectal cancers with MSI contain subpopulations of cells lacking HDAC2. These can be isolated as single cell-derived, proliferating populations. Xenografted patient-derived colon cancer tissues with MSI also show variable patterns of HDAC2 expression in mice. HDAC2-positive and HDAC2-negative RKO cells respond similarly to pharmacological inhibitors of the class I HDACs HDAC1/HDAC2/HDAC3. In contrast to this similarity, HDAC2-negative and HDAC2-positive RKO cells undergo differential cell cycle arrest and apoptosis induction in response to the frequently used chemotherapeutic 5-fluorouracil, which becomes incorporated into and damages RNA and DNA. 5-fluorouracil causes an enrichment of HDAC2-negative RKO cells in vitro and in a subset of primary colorectal tumors in mice. 5-fluorouracil induces the phosphorylation of KAP1, a target of the checkpoint kinase ataxia-telangiectasia mutated (ATM), stronger in HDAC2-negative cells than in their HDAC2-positive counterparts. Pharmacological inhibition of ATM sensitizes RKO cells to cytotoxic effects of 5-fluorouracil. These findings demonstrate that HDAC2 and ATM modulate the responses of colorectal cancer cells towards 5-FU.

Prenatal benzo[a]pyrene exposure impairs hippocampal synaptic plasticity and cognitive function in SD rat offspring during adolescence and adulthood via HDAC2-mediated histone deacetylation.

Benzo[a]pyrene (B[a]P) is a widespread carcinogenic pollutant in the environment. Although previous studies have demonstrated the neurodevelopmental toxicity of B[a]P, the precise mechanisms underlying the neurotoxic effects induced by prenatal B[a]P exposure remain largely unknown. In the present study, pregnant Sprague-Dawley (SD) rats were injected intraperitoneally with 0, 10, 20, or 40 mg/kg-bw of B[a]P for three consecutive days on embryonic days 17-19. The learning and memory abilities of offspring were determined by Morris Water Maze (MWM) test, while the number of dendritic branches and the density of dendritic spines in hippocampal CA1 and DG regions were evaluated by Golgi-Cox staining at PND 45 and PND 75. The mRNA expression of BDNF, PSD-95, and SYP in offspring hippocampus were detected by qRT-PCR, and the protein expression of BDNF, PSD-95, SYP, HDAC2, acH3K9, and acH3K14 were measured by Western blotting or immunohistochemistry. CHIP-PCR was performed to further detect the levels of acH3K9 and acH3K14 in the promoter regions of BDNF and PSD-95 genes. Our results showed that rats prenatally exposed to B[a]P exhibited impaired spatial learning and memory abilities and the number of dendritic branches and the density of dendritic spines in the hippocampal CA1 and DG regions were significantly reduced during adolescence and adulthood. The expression of HDAC2 protein was significantly upregulated, while acH3K9, acH3K14, BDNF, PSD-95, and SYP protein levels were significantly downregulated in the hippocampus of B[a]P- exposed rats. In addition, CHIP results showed that prenatal B[a]P exposure markedly decreased the level of acH3K9 and acH3K14 in the promoter region of BDNF and PSD-95 gene in the hippocampus of PND 45 and PND 75 offspring. All of the results suggest that prenatal B[a]P exposure impairs cognitive function and hippocampal synaptic plasticity of offspring in adolescence and adulthood, and HDAC2-mediated histone deacetylation plays a crucial role in these deficits.