Chitosan/dextran-based organohydrogel delivers EZH2 inhibitor to epigenetically reprogram chemo/immuno-resistance in unresectable metastatic melanoma.

Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

Hyperactivating EZH2 to augment H3K27me3 levels in regulatory T cells enhances immune suppression by driving early effector differentiation.

The immunosuppressive function of regulatory T (Treg) cells is essential for maintaining immune homeostasis. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methyltransferase, plays a key role in maintaining Treg cell function upon CD28 co-stimulation, and Ezh2 deletion in Treg cells causes autoimmunity. Here, we assess whether increasing H3K27me3 levels, by using an Ezh2Y641F gain-of-function mutation, will improve Treg cell function. We find that Treg cells expressing Ezh2Y641F display an effector Treg phenotype, are poised for improved homing to organ tissues, and can accelerate remission from autoimmunity. The H3K27me3 landscape and transcriptome of naive Ezh2Y641F Treg cells exhibit a redistribution of H3K27me3 modifications that recapitulates the gene expression profile of activated Ezh2WT Treg cells after CD28 co-stimulation. Altogether, increased H3K27me3 levels promote the differentiation of effector Treg cells that can better suppress autoimmunity.

Functional role of lncRNA MEG3 on pyroptosis through interacting with EZH2 and YTHDC1 in postoperative cognitive dysfunction.

BACKGROUND: The molecular biology mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear, resulting in a lack of specific therapeutic targets and limited clinical treatment options. The NLRP3 pyroptotic pathway, induced by neuroinflammation, is known to promote the development of POCD. Research has shown that lncRNA MEG3 exacerbates cell pyroptosis in various neurological injuries, though the precise mechanism remains to be investigated. METHODS: In vitro and in vivo models of POCD were established through treatment with sevoflurane. Gene and protein expression were investigated using qRT-PCR, Western blot analysis, ELISA, and histological staining. Additionally, cell viability and injury were assessed through CCK-8 and LDH assays. Hippocampal-dependent memory and cognitive abilities were evaluated using the Morris Water Maze (MWM) test. Furthermore, the interactions between MEG3 and EZH2/YTHDC1 were validated through RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP). RESULTS: Our findings reveal that sevoflurane significantly reduced MEG3 and pyroptosis-related proteins in mice. The overexpression of MEG3 protected mice against sevoflurane-induced cognitive dysfunction and reversed sevoflurane-induced pyroptosis in hippocampal neurons. MEG3 induced the downregulation of NLRP3 expression and reduced mRNA stability through its interaction with EZH2/YTHDC1. CONCLUSION: In conclusion, our study elucidates that MEG3 inhibits the NLRP3 inflammasome and hippocampal neuron pyroptosis through the recruitment of EZH2/YTHDC1. These findings shed light on the underlying mechanism of MEG3 in the regulation of POCD and suggest that MEG3 could serve as a potential therapeutic target for the treatment of POCD.

A new digital droplet PCR method for looking at epigenetics in diffuse large B-cell lymphomas: The role of BMI1, EZH2, and USP22 genes.

INTRODUCTION: Epigenetics has been shown to be relevant in oncology: BMI1 overexpression has been reported in leukemias, EZH2 mutations have been found in follicular lymphoma, and USP22 seems to stabilize BMI1 protein. In this study, we measured the expression of BMI1, EZH2, and USP22 in lymph nodes from 56 diffuse large B-cell lymphoma (DLBCL) patients. METHODS: A new multiplex digital droplet PCR (ddPCR) has been set up to measure the expression of 4 genes (BMI1, EZH2, USP22, and GAPDH) in the same reaction on RNA extracted from paraffin-embedded tissues. RESULTS: The specificity of ddPCR was confirmed by a 100% alignment on the BLAST platform and its repeatability demonstrated by duplicates. A strict correlation between expression of BMI1 and EZH2 and BMI1 and USP22 has been found, and high expression of these genes was correlated with extra-nodal lymphomas. Progression-free survival (PFS) and overall survival (OS) were conditioned by IPI, bone marrow infiltration, and the complete response achievement. High levels of BMI1 and USP22 did not condition the response to therapy, but impaired the PFS, especially for patients defined at "high risk" based on the cell of origin (no germinal center [GCB]), high BCL2 expression, and IPI 3-5. In this subgroup, the probability of relapse/progression was twice higher than that of patients carrying low BMI1 and USP22 levels. CONCLUSION: High expression of BMI1 and of USP22 might be a poor prognostic factor in DLBCL, and might represent the target for novel inhibitors.

Lonicerin alleviates intestinal myenteric neuron injury induced by hypoxia/reoxygenation treated macrophages by downregulating EZH2.

Intestinal ischemia-reperfusion (IR) injury is a common gastrointestinal disease that induces severe intestinal dysfunction. Intestinal myenteric neurons participate in maintaining the intestinal function, which will be severely injured by IR. Macrophages are widely reported to be involved in the pathogenesis of organ IR injury, including intestine, which is activated by NLRP3 signaling. Lonicerin (LCR) is a natural extracted monomer with inhibitory efficacy against the NLRP3 pathway in macrophages. The present study aims to explore the potential protective function of LCR in intestinal IR injury. Myenteric neurons were extracted from mice. RAW 264.7 cells were stimulated by H/R with or without 10 µM and 30 µM LCR. Remarkable increased release of IL-6, MCP-1, and TNF-α were observed in H/R treated RAW 264.7 cells, along with an upregulation of NLRP3, cleaved-caspase-1, IL-1ß, and EZH2, which were sharply repressed by LCR. Myenteric neurons were cultured with the supernatant collected from each group. Markedly decreased neuron number and shortened length of neuron axon were observed in the H/R group, which were signally reversed by LCR. RAW 264.7 cells were stimulated by H/R, followed by incubated with 30 µM LCR with or without pcDNA3.1-EZH2. The inhibition of LCR on NLRP3 signaling in H/R treated RAW 264.7 cells was abolished by EZH2 overexpression. Furthermore, the impact of LCR on neuron number and neuron axon length in myenteric neurons in the H/R group was abated by EZH2 overexpression. Collectively, LCR alleviated intestinal myenteric neuron injury induced by H/R treated macrophages via downregulating EZH2.

Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells.

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

CBX2 enhances the progression and TMZ chemoresistance of glioma via EZH2-mediated epigenetic silencing of PTEN expression.

Chromobox (CBX) 2, a member of the CBX protein family and a crucial component of the polycomb repressive complex (PRC), exerts significant influence on the epigenetic regulation of tumorigenesis, including glioma. However, the precise role of CBX2 in glioma has remained elusive. In our study, we observed a substantial upregulation of CBX2 expression in glioma, which displayed a strong correlation with pathological grade, chemoresistance, and unfavorable prognosis. Through a series of in vivo and in vitro experiments, we established that heightened CBX2 expression facilitated glioma cell proliferation and bolstered resistance to chemotherapy. Conversely, CBX2 knockdown led to a significant inhibition of glioma cell growth and a reduction in chemoresistance. Notably, our investigation uncovered the underlying mechanism by which CBX2 operates, primarily by inhibiting PTEN transcription and activating the AKT/mTOR signalling pathway. Conversely, silencing CBX2 curtailed cell proliferation and attenuated chemoresistance by impeding the activation of the PTEN/AKT/mTOR signalling pathway. Delving deeper into the molecular intricacies, we discovered that CBX2 can recruit EZH2 and modulate the trimethylation of histone H3 lysine 27 (H3K27me3) levels on the PTEN promoter, effectively suppressing PTEN transcription. Our research unveils a comprehensive understanding of how CBX2 impacts the tumorigenesis, progression, chemoresistance, and prognosis of glioma. Furthermore, it presents CBX2 as a promising therapeutic target for drug development and clinical management of glioma.

MTF2 facilitates the advancement of osteosarcoma through mediating EZH2/SFRP1/Wnt signaling.

BACKGROUND: Osteosarcoma is a soft tissue neoplasm with elevated recurrence risk and highly metastatic potential. Metal response element binding transcriptional factor 2 (MTF2) has been revealed to exert multiple activities in human tissues. The present research was conducted to explore the functions and related response mechanism of MTF2 in osteosarcoma which have not been introduced yet. METHODS: Bioinformatics tools identified the differential MTF2 expression in osteosarcoma tissues. MTF2 expression in osteosarcoma cells was examined with Western blot. Cell Counting Kit-8 (CCK-8) assay, 5-Ethynyl-2'-deoxyuridine (EDU) staining, wound healing as well as transwell assays measured cell proliferation, migration and invasion, respectively. Flow cytometry assay detected the cellular apoptotic level. Western blot also measured the expressions of proteins associated with epithelial mesenchymal transition (EMT), apoptosis and enhancer of zeste homolog 2 (EZH2)/secreted frizzled-related protein 1 (SFRP1)/Wnt signaling. Co-immunoprecipitation (Co-IP) assay confirmed MTF2-EZH2 interaction. RESULTS: MTF2 expression was increased in osteosarcoma tissues and cells. MTF2 interference effectively inhibited the proliferation, migration and invasion of osteosarcoma cells and promoted the cellular apoptotic rate. MTF2 directly bound to EZH2 and MTF2 silence reduced EZH2 expression, activated SFRP1 expression and blocked Wnt signaling in osteosarcoma cells. EZH2 upregulation or SFRP1 antagonist WAY-316606 partly counteracted the impacts of MTF2 down-regulation on the SFRP1/Wnt signaling and the biological phenotypes of osteosarcoma cells. CONCLUSIONS: MTF2 might down-regulate SFRP1 to activate Wnt signaling and drive the progression of osteosarcoma via interaction with EZH2 protein.

Identification of Poliovirus Receptor-like 3 Protein as a Prognostic Factor in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) represents an aggressive subtype of breast cancer, with a bad prognosis and lack of targeted therapeutic options. Characterized by the absence of estrogen receptors, progesterone receptors, and HER2 expression, TNBC is often associated with a significantly lower survival rate compared to other breast cancer subtypes. Our study aimed to explore the prognostic significance of 83 immune-related genes, by using transcriptomic data from the TCGA database. Our analysis identified the Poliovirus Receptor-Like 3 protein (PVRL3) as a critical negative prognostic marker in TNBC patients. Furthermore, we found that the Enhancer of Zeste Homolog 2 (EZH2), a well-known epigenetic regulator, plays a pivotal role in modulating PVRL3 levels in TNBC cancer cell lines expressing EZH2 along with high levels of PVRL3. The elucidation of the EZH2-PVRL3 regulatory axis provides valuable insights into the molecular mechanisms underlying TNBC aggressiveness and opens up potential pathways for personalized therapeutic intervention.

Tazemetostat for relapsed/refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan: 3-year follow-up for a phase II study.

Previously, we reported the efficacy and safety of tazemetostat in Japanese patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) harboring the EZH2 mutation in a multicenter, open-label, phase II study. Here, we present a follow-up analysis of tazemetostat at a long-term median follow-up of 35.0 months. Twenty patients were enrolled: 17 in the FL cohort and three in the DLBCL cohort. In the FL cohort, the objective response rate was 70.6%, consistent with the primary analysis, and the median progression-free survival (PFS) was not reached. The 24-month and 36-month PFS rates were 72.1% (95% confidence interval [CI] 41.5%-88.6%) and 64.1% (95% CI 33.7%-83.4%), respectively. The median duration of treatment was 30.2 months. After the primary analysis at a median follow-up of 12.9 months, grade 1-2 urinary tract infection, peripheral motor neuropathy, and hypogammaglobulinemia newly emerged, but the incidence of adverse events (AEs) did not increase notably during this follow-up period. No unexpected grade ≥ 3 treatment-related AEs were reported. Long-term oral monotherapy with tazemetostat showed favorable efficacy and safety profiles, indicating that it may be a useful third-line or later treatment option for patients with relapsed/refractory FL harboring the EZH2 mutation. Trial registration: ClinicalTrials.gov: NCT03456726.

Computed tomography-based radiomics predicts the fibroblast-related gene EZH2 expression level and survival of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer. The primary treatment strategies for HCC currently include liver transplantation and surgical resection. However, these methods often yield unsatisfactory outcomes, leading to a poor prognosis for many patients. This underscores the urgent need to identify and evaluate novel therapeutic targets that can improve the prognosis and survival rate of HCC patients. AIM: To construct a radiomics model that can accurately predict the EZH2 expression in HCC. METHODS: Gene expression, clinical parameters, HCC-related radiomics, and fibroblast-related genes were acquired from public databases. A gene model was developed, and its clinical efficacy was assessed statistically. Drug sensitivity analysis was conducted with identified hub genes. Radiomics features were extracted and machine learning algorithms were employed to generate a radiomics model related to the hub genes. A nomogram was used to illustrate the prognostic significance of the computed Radscore and the hub genes in the context of HCC patient outcomes. RESULTS: EZH2 and NRAS were independent predictors for prognosis of HCC and were utilized to construct a predictive gene model. This model demonstrated robust performance in diagnosing HCC and predicted an unfavorable prognosis. A negative correlation was observed between EZH2 expression and drug sensitivity. Elevated EZH2 expression was linked to poorer prognosis, and its diagnostic value in HCC surpassed that of the risk model. A radiomics model, developed using a logistic algorithm, also showed superior efficiency in predicting EZH2 expression. The Radscore was higher in the group with high EZH2 expression. A nomogram was constructed to visually demonstrate the significant roles of the radiomics model and EZH2 expression in predicting the overall survival of HCC patients. CONCLUSION: EZH2 plays significant roles in diagnosing HCC and therapeutic efficacy. A radiomics model, developed using a logistic algorithm, efficiently predicted EZH2 expression and exhibited strong correlation with HCC prognosis.

The role of deubiquitinase USP2 in driving bladder cancer progression by stabilizing EZH2 to epigenetically silence SOX1 expression.

BACKGROUND: The Ubiquitin-proteasome system (UPS) is known to participate in multiple cellular events. The deubiquitinating enzyme USP2 (ubiquitin-specific protease 2) is involved in the vasculature remodeling process associated with bladder cancer (BLCA). However, the role of USP2 in BLCA progression has not been clearly defined and whether its regulatory mechanism involving EZH2 (Enhancer of Zeste Homolog 2) remains elusive yet. METHODS: Differential expression patterns of USP2 and EZH2 were examined in 46 pairs of BLCA and adjacent normal tissues. USP2 knockdown plasmids were transfected into 5637 and J82 cells to detect its impact on cell proliferation, migration and invasion using CCK-8, EdU, wound healing and transwell assays. The USP2-EZH2-SOX1 cascade was confirmed through Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays. An in vivo verification was conducted using a xenograft model of nude mice. RESULTS: USP2 was significantly upregulated in BLCA tissues and cells, which was associated with poor clinical prognosis in BLCA patients. USP2 depletion resulted in decreased cell proliferation, migration and invasion in BLCA cells. USP2 stabilized the EZH2 protein by directly binding to it, thereby reducing its ubiquitination. Ectopic introduction of EZH2 restored cell growth and invasion of BLCA cells, which had been inhibited by USP2 silencing. USP2-mediated stabilization of EZH2 promoted the enrichment of histone H3K27me3 and repression of SOX1. Involvement of the USP2-EZH2-SOX1 axis in tumor formation was ultimately verified in vivo. CONCLUSION: Our findings reveal that a USP2-EZH2-SOX1 axis orchestrates the interplay between dysregulated USP2 and EZH2-mediated gene epigenetic silencing in BLCA progression.

Potential mechanism of Luoshi Neiyi prescription in endometriosis based on serum pharmacochemistry and network pharmacology.

Introduction: Endometriosis (EMs) is characterized by ectopic growth of active endometrial tissue outside the uterus. The Luoshi Neiyi prescription (LSNYP) has been extensively used for treating EMs in China. However, data on the active chemical components of LSNYP are insufficient, and its pharmacological mechanism in EMs treatment remains unclear. This study aimed to explore the potential mechanism of LSNYP for EMs through network pharmacology based on the components absorbed into the blood. Methods: Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to analyze blood components, and a series of network pharmacology strategies were utilized to predict targets of these components and EMs. Protein-protein interaction (PPI) network analysis, component-target-disease network construction, gene ontology (GO) functional enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Additionally, molecular docking, molecular dynamics simulations, and in vitro and in vivo experiments were conducted to validate the HIF1A/EZH2/ANTXR2 pathway associated with hypoxic pathology in EMs. Results: Thirty-four absorbed components suitable for network pharmacology analysis were identified, and core targets, such as interleukin 6, EGFR, HIF1A, and EZH2, were founded. Enrichment results indicated that treatment of EMs with LSNYP may involve the regulation of hypoxia and inflammatory-related signaling pathways and response to oxidative stress and transcription factor activity. Experimental results demonstrated that LSNYP could decrease the expression of HIF1A, ANTXR2, YAP1, CD44, and ß-catenin, and increased EZH2 expression in ectopic endometrial stromal cells and endometriotic tissues. Molecular docking and molecular dynamics simulations manifested that there was stable combinatorial activity between core components and key targets of the HIF1A/EZH2/ANTXR2 pathway. Conclusion: LSNYP may exert pharmacological effects on EMs via the HIF1A/EZH2/ANTXR2 pathway; hence, it is a natural herb-related therapy for EMs.

Mesenchymal stem cell-derived exosomal microRNA-367-3p mitigates lower limb ischemia/reperfusion injury in mouse skeletal muscle via EZH2 targeting.

OBJECTIVE: This study aimed to investigate the protective effect of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-exo) against lower limb ischemia/reperfusion (I/R) injury-induced pyroptosis in skeletal muscle. METHODS: A mouse model of lower limb I/R injury was utilized to assess the impact of BMSCs-exo, particularly when loaded with microRNA-367-3p (miR-367-3p), on pyroptosis. Histological examination, wet weight/dry weight ratio measurements, and luciferase assays were employed to elucidate the mechanisms involved. KEY FINDINGS: BMSCs-exo effectively suppressed pyroptosis in injured skeletal muscle tissue. Loading BMSCs-exo with miR-367-3p enhanced this protective effect by downregulating key pyroptosis-related proteins. Luciferase assays identified enhancer of zeste homolog 2 (EZH2) as a direct target of miR-367-3p in BMSCs-exo. CONCLUSIONS: BMSCs-exo loaded with miR-367-3p safeguarded mouse skeletal muscle against pyroptosis-induced I/R injury by targeting EZH2. These findings offer valuable insights into potential therapeutic strategies for lower limb I/R injuries, emphasizing the therapeutic potential of BMSCs-exo in mitigating tissue damage caused by pyroptosis.

Bisphenol S (BPS) induces glioblastoma progression via regulation of EZH2-mediated PI3K/AKT/mTOR pathway in U87-MG cells.

Bisphenol S (BPS), an alternative to bisphenol A (BPA), exerts proliferative effects similar to those of BPA. BPS is a representative endocrine disruptor associated with cancer progression. However, the mechanisms underlying BPS-induced glioblastoma progression are not fully understood. To investigate the effects of BPS on glioblastoma, U-87 MG cancer cell lines were exposed to BPS. The study focused on analyzing the proliferation and migration of U-87 MG cells. Furthermore, the involvement of the enhancer of the zeste homolog 2 (EZH2)-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) pathway was examined. Pharmacological approaches were employed to inhibit EZH2 activity and observe its effects on BPS-induced changes. The results indicated that BPS promoted the proliferation and migration of U-87 MG cells at a concentration of 0.1 µM. These changes appeared to be linked to the activation of the EZH2-mediated PI3K/AKT/mTOR pathway. Moreover, inhibiting EZH2 activity using pharmacological approaches restored the BPS-mediated induction of proliferation and migration. In conclusion, the results of this study indicated that BPS induces glioblastoma progression through EZH2 upregulation. Therefore, targeting the EZH2-mediated PI3K/AKT/mTOR pathway could be considered a potential therapeutic strategy for the treatment of glioblastoma.

Immunomodulator-Derived Nanoparticles Induce Neuroprotection and Regulatory T Cell Action to Alleviate Parkinsonism.

Post-translational modification, mitochondrial abruptions, neuroinflammation, and α-synuclein (α-Syn) aggregation are considered as major causes of Parkinson's disease (PD) pathogenesis. The recent literature highlights neuroimmune cross talk and the negative role of immune effector T (Teff) and positive regulation by regulatory T (Treg) cells in PD treatment. Herein, a strategy to endow Treg action paves the path for development of PD treatment. Thus, we explored the neuroprotective efficiency of the immunomodulator and PP2A (protein phosphatase 2) activator, FTY720 nanoparticles in in vivo experimental PD models. Repurposing of FTY720 for PD is known due to its protective effect by reducing PD and its camouflaged role in endowing EZH2-mediated epigenetic regulation of PD. EZH2-FOXP3 interaction is necessary for the neuroprotective Treg cell activity. Therefore, we synthesized FTY720 nanoparticles to improve FTY720 protective efficacy in an in vivo PD model to explore the PP2A mediated signaling. We confirmed the formation of FTY720NPs, and the results of the behavioral and protein expression study showed the significant neuroprotective efficiency of our nanoformulations. In the exploration of neuroprotective mechanism, several lines of evidence confirmed FTY720NPs mediated induction of PP2A/EZH2/FOXP3 signaling in the induction of Treg cells effect in in vivo PD treatment. In summary, our nanoformulations have novel potential to alleviate PD by inducing PP2A-induced epigenetic regulation-mediated neuroimmunomodulation at the clinical setup.

Role of EZH2-mediated epigenetic modification on vascular smooth muscle in cardiovascular diseases: A mini-review.

Vascular smooth muscle cells (VSMCs) are integral to the pathophysiology of cardiovascular diseases (CVDs). Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, plays a crucial role in epigenetic regulation of VSMCs gene expression. Emerging researches suggest that EZH2 has a dual role in VSMCs, contingent on the pathological context of specific CVDs. This mini-review synthesizes the current knowledge on the mechanisms by which EZH2 regulates VSMC proliferation, migration and survival in the context of CVDs. The goal is to underscore the potential of EZH2 as a therapeutic target for CVDs treatment. Modulating EZH2 and its associated epigenetic pathways in VSMCs could potentially ameliorate vascular remodeling, a key factor in the progression of many CVDs. Despite the promising outlook, further investigation is warranted to elucidate the epigenetic mechanisms mediated by EZH2 in VSMCs, which may pave the way for novel epigenetic therapies for conditions such as atherosclerosis and hypertension.

The role of EZH2 and its regulatory lncRNAs as a serum-based biomarker in Alzheimer's disease.

BACKGROUND: Long noncoding RNAs (lncRNAs) have become a hot topic in the human nervous system. Moreover, circulating lncRNAs have been suggested as possible biomarkers for central nervous system processes and neurodegenerative diseases. The present research aimed to highlight the role of plasma lncRNAs TUG1, FEZF1-AS1, and EZH2 gene as diagnostic biomarkers in Alzheimer's disease (AD). METHODS: Plasma samples for the study were provided by 100 AD patients and 100 matched controls. Real-time quantitative reverse transcriptase PCR was used to determine the plasma level of the aforementioned lncRNAs. Furthermore, the plasma level of EZH2 protein in the participants' blood was determined using the ELISA technique. RESULTS: In contrast to controls, down-regulation of the EZH2 gene and protein was reported in the plasma of patients with AD. Additionally, plasma samples from AD patients showed up-and-down-regulation of the lncRNAs TUG1 and FEZF1-AS1, respectively. CONCLUSION: Our new findings suggest that the EZH2 gene, plasma lncRNA TUG1, and FEZF1-AS1 may contribute, as valuable biomarkers, to AD diagnosis.

Androgen-Induced, ß-Catenin-Activated Hepatocellular Adenomatosis with Spontaneous External Rupture.

Androgens have long been recognized as oncogenic agents. They can induce both benign and malignant hepatocellular neoplasms, including hepatocellular adenoma (HCA) and hepatocellular carcinoma, though the underlying mechanisms remain unclear. Androgen-induced liver tumors are most often solitary and clinically silent. Herein, we reported an androgen-induced HCA complicated by spontaneous rupture. The patient was a 24-year-old male presenting with fatigue, diminished libido, radiology-diagnosed hepatocellular adenomatosis for 3 years, and sudden-onset, severe, sharp, constant abdominal pain for one day. He used Aveed (testosterone undecanoate injection) from age 17 and completely stopped one year before his presentation. A physical exam showed touch pain and voluntary guarding in the right upper quadrant of the abdomen. An abdominal CT angiogram demonstrated multiple probable HCAs, with active hemorrhage of the largest one (6.6 × 6.2 × 5.1 cm) accompanied by large-volume hemoperitoneum. After being stabilized by a massive transfusion protocol and interventional embolization, he underwent a percutaneous liver core biopsy. The biopsy specimen displayed atypical hepatocytes forming dense cords and pseudoglands. The lesional cells diffusely stained ß-catenin in nuclei and glutamine synthetase in cytoplasm. Compared to normal hepatocytes from control tissue, the tumor cells were positive for nuclear AR (androgen receptor) expression but had no increased EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit) protein expression. The case indicated that androgen-induced hepatocellular neoplasms should be included in the differential diagnosis of acute abdomen.

Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.

BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated undernutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC; gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg intraperitoneally twice a day for 3 weeks). Gastric ICC were analyzed by Western blotting and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.