Discovery of an EP300 Inhibitor using Structure-based Virtual Screening and Bioactivity Evaluation.

BACKGROUND: EP300 (E1A binding protein p300) played a significant role in serial diseases such as cancer, neurodegenerative disease. Therefore, it became a significant target. METHODS: Targeting EP300 discovery of a novel drug to alleviate these diseases. In this paper, 17 candidate compounds were obtained using a structure-based virtual screening approach, 4449-0460, with an IC50 of 5.89 ± 2.08 uM, which was identified by the EP300 bioactivity test. 4449-0460 consisted of three rings. The middle benzene ring connected the 5-ethylideneimidazolidine-2,4-dione group and the 3-F-Phenylmethoxy group. RESULTS: Furthermore, the interaction mechanism between 4449-0460 and EP300 was explored by combining molecular dynamics (MD) simulations and binding free energy calculation methods. CONCLUSION: The binding free energy of EP300 with 4449-0460 was -10.93 kcal/mol, and mainly came from the nonpolar energy term (ΔGnonpolar). Pro1074, Phe1075, Val1079, Leu1084, and Val1138 were the key residues in EP300/4449-0460 binding with more -1 kcal/mol energy contribution. 4449-0460 was a promising inhibitor targeting EP300, which had implications for the development of drugs for EP300-related diseases.

EP300 promotes tumor stemness via epigenetic activation of CRISP3 leading to lobaplatin resistance in triple-negative breast cancer.

Lobaplatin shows antitumor activity against a wide range of tumors, including triple-negative breast cancer (TNBC), and has been linked to cancer stem cell pool. Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC.

EP300 through upregulating the expression of vimentin to promote the progression of chordoma.

OBJECTIVE: There is a lack of effective drugs to treat the progression and recurrence of chordoma, which is widely resistant to treatment in chemotherapy. The authors investigated the functional and therapeutic relevance of the E1A-binding protein p300 (EP300) in chordoma. METHODS: The expression of EP300 and vimentin was examined in specimens from 9 patients with primary and recurrent chordoma with immunohistochemistry. The biological functions of EP300 were evaluated with Cell Counting Kit-8, clonogenic assays, and transwell assays. The effects of EP300 inhibitors (C646 and SGC-CBP30) on chordoma cell motility were assessed with these assays. The effect of the combination of EP300 inhibitors and cisplatin on chordoma cells was evaluated with clonogenic assays. Reverse transcription quantitative polymerase chain reaction and Western blot techniques were used to explore the potential mechanism of EP300 through upregulation of the expression of vimentin to promote the progression of chordoma. RESULTS: Immunohistochemistry analysis revealed a positive correlation between elevated EP300 expression levels and recurrence. The upregulation of EP300 stimulated the growth of and increased the migratory and invasive capabilities of chordoma cells, along with upregulating vimentin expression and consequently impacting their invasive properties. Conversely, EP300 inhibitors decreased cell proliferation and downregulated vimentin. Furthermore, the combination of EP300 inhibition and cisplatin exhibited an enhanced anticancer effect on chordoma cells, indicating that EP300 may influence chordoma sensitivity to chemotherapy. CONCLUSIONS: These findings indicate that EP300 functions as an oncogene in chordoma. Targeting EP300 offers a novel approach to the development and clinical treatment of chordoma.

Pathogenic hyperactivation of mTORC1 by cytoplasmic EP300 in Hutchinson-Gilford progeria syndrome.

In a recent issue in Nature Cell Biology, Sung Min Son et al. unveil a novel layer in the regulation of the mTORC1/autophagy axis by EP300 which can undergo nucleocytoplasmic shuttling in response to alterations in nutrient availability. The study highlights that, in Hutchinson-Gilford progeria syndrome, overabundant cytoplasmic EP300 results in mTORC1 hyperactivation and impaired autophagy, potentially contributing to premature and accelerated aging.

Possible New Candidates Involved to Thalidomide-Related Limbs and Cardiac Defects: A Systems Biology Approach.

Thalidomide is a known teratogen that causes malformations especially in heart and limbs. Its mechanism of teratogenicity is still not fully elucidated. Recently, a new target of thalidomide was described, TBX5, and was observed a new interaction between HAND2 and TBX5 that is disrupted in the presence of thalidomide. Therefore, our study aimed to raise potential candidates for thalidomide teratogenesis, through systems biology, evaluating HAND2 and TBX5 interaction and heart and limbs malformations of thalidomide. Genes and proteins related to TBX5 and HAND2 were selected through TF2DNA, REACTOME, Human Phenotype Ontology, and InterPro databases. Networks were assembled using STRING © database. Network analysis were performed in Cytoscape © and R v3.6.2. Differential gene expression (DGE) analysis was performed through gene expression omnibus. We constructed a network for HAND2 and TBX5 interaction; a network for heart and limbs malformations of TE; and the two joined networks. We observed that EP300 protein seemed to be important in all networks. We also looked for proteins containing C2H2 domain in the assembled networks. ZIC3, GLI1, GLI3, ZNF148, and PRDM16 were the ones present in both heart and limbs malformations of TE networks. Furthermore, in the DGE analysis after treatment with thalidomide, we observed that FANCB, ESCO2, and XRCC2 were downregulated and present both in heart and limbs networks. Through systems biology, we were able to point to different new proteins and genes, and selected specially EP300, which was important in all the analyzed networks, to be further evaluated in the TE teratogenicity.

EP300-ZNF384 transactivates IL3RA to promote the progression of B-cell acute lymphoblastic leukemia.

The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.

EP300/CREBBP acetyltransferase inhibition limits steroid receptor and FOXA1 signaling in prostate cancer cells.

The androgen receptor (AR) is a primary target for treating prostate cancer (PCa), forming the bedrock of its clinical management. Despite their efficacy, resistance often hampers AR-targeted therapies, necessitating new strategies against therapy-resistant PCa. These resistances involve various mechanisms, including AR splice variant overexpression and altered activities of transcription factors like the glucocorticoid receptor (GR) and FOXA1. These factors rely on common coregulators, such as EP300/CREBBP, suggesting a rationale for coregulator-targeted therapies. Our study explores EP300/CREBBP acetyltransferase inhibition's impact on steroid receptor and FOXA1 signaling in PCa cells using genome-wide techniques. Results reveal that EP300/CREBBP inhibition significantly disrupts the AR-regulated transcriptome and receptor chromatin binding by reducing the AR-gene expression. Similarly, GR's regulated transcriptome and receptor binding were hindered, not linked to reduced GR expression but to diminished FOXA1 chromatin binding, restricting GR signaling. Overall, our findings highlight how EP300/CREBBP inhibition distinctively curtails oncogenic transcription factors' signaling, suggesting the potential of coregulatory-targeted therapies in PCa.

EP300 regulates the SLC16A1-AS1-AS1/TCF3 axis to promote lung cancer malignancies through the Wnt signaling pathway.

Objective: To investigate the regulatory mechanism of EP300 in the interaction between SLC16A1-AS1 and TCF3 to activate the Wnt pathway, thereby promoting malignant progression in lung cancer. Methods: In lung cancer cell lines, SLC16A1-AS1 was knocked down, and the impact of this knockdown on the malignant progression of lung cancer cells was assessed through clonogenic assays, Transwell assays, and apoptosis experiments. The regulatory relationship between EP300 and SLC16A1-AS1 was investigated through bioinformatic analysis and ChIP experiments. The expression of SLC16A1-AS1 and TCF3 in 56 paired lung cancer tissues was examined using RT-qPCR, and their correlation was analyzed. The interaction between TCF3 and SLC16A1-AS1 was explored through bioinformatic analysis and CoIP experiments. Activation of the Wnt/ß-catenin pathway was assessed by detecting the accumulation of ß-catenin in the nucleus through Western blotting. The role of EP300 in regulating the effect of SLC16A1-AS1/TCF3-mediated Wnt/ß-catenin signaling on lung cancer malignant progression was validated through in vitro and in vivo experiments. Results: SLC16A1-AS1 is highly expressed in lung cancer and regulates its malignant progression. EP300 mediates histone modifications on the SLC16A1-AS1 promoter, thus controlling its expression. SLC16A1-AS1 exhibits specific interactions with TCF3, and the SLC16A1-AS1/TCF3 complex activates the Wnt/ß-catenin pathway. EP300 plays a critical role in regulating the impact of SLC16A1-AS1/TCF3-mediated Wnt/ß-catenin signaling on lung cancer malignant progression. Conclusion: EP300 regulates the SLC16A1-AS1/TCF3-mediated Wnt/ß-catenin signaling pathway, influencing the malignant progression of lung cancer.

Insights into dietary phytochemicals targeting Parkinson's disease key genes and pathways: A network pharmacology approach.

Parkinson's disease (PD) is a complex neurological disease associated with the degeneration of dopaminergic neurons. Oxidative stress is a key player in instigating apoptosis in dopaminergic neurons. To improve the survival of neurons many dietary phytochemicals have gathered significant attention recently. Thus, the present study implements a comprehensive network pharmacology approach to unravel the mechanisms of action of dietary phytochemicals that benefit disease management. A literature search was performed to identify ligands (i.e., comprising dietary phytochemicals and Food and Drug Administration pre-approved PD drugs) in the PubMed database. Targets associated with selected ligands were extracted from the search tool for interactions of chemicals (STITCH) database. Then, the construction of a gene-gene interaction (GGI) network, analysis of hub-gene, functional and pathway enrichment, associated transcription factors, miRNAs, ligand-target interaction network, docking were performed using various bioinformatics tools together with molecular dynamics (MD) simulations. The database search resulted in 69 ligands and 144 unique targets. GGI and subsequent topological measures indicate histone acetyltransferase p300 (EP300), mitogen-activated protein kinase 1 (MAPK1) or extracellular signal-regulated kinase (ERK)2, and CREB-binding protein (CREBBP) as hub genes. Neurodegeneration, MAPK signaling, apoptosis, and zinc binding are key pathways and gene ontology terms. hsa-miR-5692a and SCNA gene-associated transcription factors interact with all the 3 hub genes. Ligand-target interaction (LTI) network analysis suggest rasagiline and baicalein as candidate ligands targeting MAPK1. Rasagiline and baicalein form stable complexes with the Y205, K330, and V173 residues of MAPK1. Computational molecular insights suggest that baicalein and rasagiline are promising preclinical candidates for PD management.

Histone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy.

Lysine acetyltransferases (KATs) are a family of epigenetic enzymes involved in the regulation of gene expression; they represent a promising class of emerging drug targets. The frequent molecular dysregulation of these enzymes, as well as their mechanistic links to biological functions that are crucial to cancer, have led to exploration around the development of small-molecule inhibitors against KATs. Despite early challenges, recent advances have led to the development of potent and selective enzymatic and bromodomain (BRD) KAT inhibitors. In this review we discuss the discovery and development of new KAT inhibitors and their application as oncology therapeutics. Additionally, new chemically induced proximity approaches are presented, offering opportunities for unique target selectivity profiles and tissue-specific targeting of KATs. Emerging clinical data for CREB binding protein (CREBBP)/EP300 BRD inhibitors and KAT6 catalytic inhibitors indicate the promise of this target class in cancer therapeutics.

Acetyltransferase P300 Regulates Glucose Metabolic Reprogramming through Catalyzing Succinylation in Lung Cancer.

Aberrant protein post-translational modification is a hallmark of malignant tumors. Lysine succinylation (Ksucc) plays a vital role in cell energy metabolism in various cancers. However, whether succinylation can be catalyzed by acetyltransferase p300 remains unclear. In this study, we unveiled that p300 is a "writer" for succinylation, and p300-mediated Ksucc promotes cell glycometabolism in lung adenocarcinoma (LUAD). Specifically, our succinylome data revealed that EP300 deficiency leads to the systemic reduction of Ksucc, and 79.55% of the p300-succinylated proteins were found in the cytoplasm, which were primarily enriched in the carbohydrate metabolism process. Interestingly, deleting EP300 led to a notable decrease in Ksucc levels on several glycolytic enzymes, especially Phosphoglycerate Kinase 1 (PGK1). Mutation of the succinylated site of PGK1 notably hindered cell glycolysis and lactic acid excretion. Metabolomics in vivo indicated that p300-caused metabolic reprogramming was mainly attributed to the altered carbohydrate metabolism. In addition, 89.35% of LUAD patients exhibited cytoplasmic localization of p300, with higher levels in tumor tissues than adjacent normal tissues. High levels of p300 correlated with advanced tumor stages and poor prognosis of LUAD patients. Briefly, we disclose the activity of p300 to catalyze succinylation, which contributes to cell glucose metabolic reprogramming and malignant progression of lung cancer.

Global crotonylome identifies EP300-regulated ANXA2 crotonylation in cumulus cells as a regulator of oocyte maturation.

Lysine crotonylation (Kcr), a newly discovered post-translational modification, played a crucial role in physiology and disease progression. However, the roles of crotonylation in oocyte meiotic resumption remain elusive. As abnormal cumulus cell development will cause oocyte maturation arrest and female infertility, we report that cumulus cells surrounding human meiotic arrested oocytes showed significantly lower crotonylation, which was associated with decreased EP300 expression and blocked cumulus cell expansion. In cultured human cumulus cells, exogenous crotonylation or EP300 activator promoted cell proliferation and reduced cell apoptosis, whereas EP300 knockdown induced the opposite effect. Transcriptome profiling analysis in human cumulus cells indicated that functions of crotonylation were associated with activation of epidermal growth factor receptor (EGFR) pathway. Importantly, we characterized the Kcr proteomics landscape in cumulus cells by LC-MS/MS analysis, and identified that annexin A2 (ANXA2) was crotonylated in cumulus cells in an EP300-dependent manner. Crotonylation of ANXA2 enhanced the ANXA2-EGFR binding, and then activated the EGFR pathway to affect cumulus cell proliferation and apoptosis. Using mouse oocytes IVM model and EP300 knockout mice, we further confirmed that crotonylation alteration in cumulus cells affected the oocyte maturation. Together, our results indicated that EP300-mediated crotonylation is important for cumulus cells functions and oocyte maturation.

Genotype-phenotype analysis of ocular findings in Rubinstein-Taybi syndrome - A case report and review of literature.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare genetic syndrome with a wide range of phenotypic presentations, including characteristic facial features. A variety of ocular abnormalities have been described in patients with RSTS. The genetic etiology of RSTS is heterogeneous but often involves two major genes, CREBBP (cAMP-response element binding protein-binding protein) and EP300 (E1A binding protein p300), with CREBBP variants responsible for the majority of the cases. MATERIALS AND METHODS: We report a new case of female patient with a novel variant in CREBBP (c.4495C>G), with clinical features consistent with RSTS. We performed a literature review to search for possible genotype-phenotype relationships between the type of variant in CREBBP and frequency of ocular presentations. A PubMed search generated 12 articles that met our inclusion criteria. With the addition of our patient, there were a total of 163 patients included for mutation analysis (164 variants given one patient had two different variants). RESULTS: Our review revealed that the most common variant types were frameshift (25%), gross deletion (23%), nonsense (18%), and intragenic deletions (13%). There does not appear to be an obvious hot spot location. A total of 127 patients were included for genotype-phenotype analysis of ocular features (36 patients were excluded as unable to discern variant type). The most frequent ocular features in patients with RSTS were down-slanting palpebral fissure (74%), arched eyebrows (56%), long eyelashes (52%), and strabismus (23%). CONCLUSIONS: Our results suggest that currently there is no clear genotype-phenotype relationship between the type of variant and frequency of associated ocular features in RSTS patients.

NDUFA8 is transcriptionally regulated by EP300/H3K27ac and promotes mitochondrial respiration to support proliferation and inhibit apoptosis in cervical cancer.

Cervical cancer, a common malignancy in women, poses a significant health burden worldwide. In this study, we aimed to investigate the expression, function, and potential mechanisms of NADH: ubiquinone oxidoreductase subunit A8 (NDUFA8) in cervical cancer. The Gene Expression Profiling Interactive Analysis (GEPIA) database and immunohistochemical scoring were used to analyze NDUFA8 expression in cervical cancer tissues and normal tissues. Quantitative real-time PCR and Western blot analyses were performed to assess the expression level of NDUFA8 in cervical cancer cell lines. NDUFA8 knockdown or overexpression experiments were conducted to evaluate its impact on cell proliferation and apoptosis. The mitochondrial respiratory status was analyzed by measuring cellular oxygen consumption, adenosine triphosphate (ATP) levels, and the expression levels of Mitochondrial Complex I activity, and Mitochondrial Complex IV-associated proteins Cytochrome C Oxidase Subunit 5B (COX5B) and COX6C. NDUFA8 exhibited high expression levels in cervical cancer tissues, and these levels were correlated with reduced survival rates. A significant upregulation of NDUFA8 expression was observed in cervical cancer cell lines compared to normal cells. Silencing NDUFA8 hindered cell proliferation, promoted apoptosis, and concurrently suppressed cellular mitochondrial respiration, resulting in decreased levels of available ATP. Conversely, NDUFA8 overexpression induced the opposite effects. Herein, we also found that E1A Binding Protein P300 (EP300) overexpression facilitated Histone H3 Lysine 27 (H3K27) acetylation enrichment, enhancing the activity of the NDUFA8 promoter region. NDUFA8, which is highly expressed in cervical cancer, is regulated by transcriptional control via EP300/H3K27 acetylation. By promoting mitochondrial respiration, NDUFA8 contributes to cervical cancer cell proliferation and apoptosis. These findings provide novel insights into NDUFA8 as a therapeutic target in cervical cancer.

EP300 promotes lung cancer cell proliferation by regulating the oncogenic transcription of Hippo-YAP signaling pathway.

The transcriptional activation function of YAP in cancer development has been widely studied. However, the underlying regulatory mechanisms remain largely unknown. In this study, we found that EP300, one histone acetyltransferase, interacted with YAP and was recruited into the phase separated condensates of YAP. Transcriptomic analysis revealed substantial alterations in gene expression upon EP300 depletion, with downregulated genes associated with cancer progression and Hippo-YAP pathway. Notably, disruption of EP300 inhibited the transcriptional activation of YAP and reduced the binding of H3K27ac on YAP target oncogenes in Hippo pathway. Moreover, depletion of EP300 effectively inhibited YAP-driven tumor growth. Taken together, these results indicate that EP300 contributes to lung cancer progression by promoting the oncogenic transcription of YAP through H3K27ac, which suggests that YAP-EP300 axis may be potential therapeutic targets for lung cancer treatment.

PPARα Senses Bisphenol S to Trigger EP300-Mediated Autophagy Blockage and Hepatic Steatosis.

The internal exposure dose of bisphenol S (BPS) is increasing since its use as a substitute for BPA. The relationship between BPS and nonalcoholic liver disease (NAFLD) and the underlying mechanism remain unclarified. In this study, we evaluated the correlation of BPS with NAFLD in populations from the Jiangsu Survey and the 2013-2016 National Health Nutrition Examination Survey and unraveled the molecular pathway by which BPS blocked hepatic autophagy, contributing to lipid accumulation. The study found that serum and urine BPS were associated with NAFLD risks in both the Chinese and US populations. For each additional unit of the BPS level, the NAFLD risk increased by 3.163-fold (serum) and 3.979-fold (urine) in the Chinese population. In addition, after BPS exposure at a dose equivalent to human exposure for 20 weeks, mice developed liver lipid accumulation. BPS could trigger PPARα-mediated transcriptional activation of EP300 expression. BPS promoted the translocation of EP300 from the nucleus to the cytoplasm to regulate the acetylation of Raptor and the activation of mTORC1, which in turn induced autophagy blockage and interfered with lipid degradation in hepatocytes. Conversely, knockdown of EP300 reduced Raptor acetylation and ameliorated autophagy blockage. This study demonstrated that EP300 was a key enzyme for the development of BPS-related NAFLD and provided novel evidence that BPS causes NAFLD.

I-CBP112 declines overexpression of ATP-binding cassette transporters and sensitized drug-resistant MDA-MB-231 and A549 cell lines to chemotherapy drugs.

Despite extensive efforts and ongoing progress in personalized anticancer approaches, chemotherapy remains the first line or the only treatment for some tumors that may develop resistance to chemotherapeutics in time due to inter alia overexpression of ATP-binding cassette transporters. Using clinically-relevant resistant models of triple negative breast cancer (MDA-MB-231; TNBC) as well as non-small cell lung cancer (A549; NSCLC), we tested the efficacy of I-CBP112 - CBP/EP300 bromodomain inhibitor to overcome drug resistance by declining ABC gene transcription. I-CBP112 significantly reduced ABCB1, ABCC1, ABCC2, ABCC3, ABCC5 and ABCG2 in all resistant lines, as well as ABCC10 in TNBC and ABCC4 in paclitaxel-resistant NSCLC, thereby increasing intracellular drug accumulation and cytotoxicity in 2D and 3D cultures. This was phenocopied only by the joint effect of ABC inhibitors such as tariquidar (ABCB1 - P-glycoprotein and ABCG2) and MK-571 (ABCC), whereas single inhibition of ABCB1/ABCG2 or ABCC proteins did not affect drug accumulation, thereby implying the need of simultaneous deficiency in activity of majority of drug pumps for enhanced drug retention. I-CBP112 failed to directly inhibit activity of ABCB1, ABCG2 and ABCC subfamily members at the same time. Importantly, I-CBP112 treated cancer cells polarized human macrophages into proinflammatory phenotypes. Moreover, I-CBP112 remained non-toxic to primary cell lines, nor did it enhance anticancer drug toxicity to blood-immune cells. In silico assay of ADMET properties confirmed the desired pharmacokinetic features of I-CBP112. The results suggest that the CBP/p300 inhibitor is a promising co-adjuvant to chemotherapy in drug-resistant cancer phenotypes, capable of decreasing ABC transporter expression.

EP300 as a Molecular Integrator of Fibrotic Transcriptional Programs.

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

Electroconvulsive Therapy Reduces Protein Expression Level of EP300 and Improves Psychiatric Symptoms and Disturbance of Thought in Patients with Schizophrenia.

Objective: Although electroconvulsive therapy (ECT) has been employed as an effective treatment strategy and to improve mental symptoms in schizophrenia (SCZ), its action mechanisms remain unclear. Our previous study found that some genes and biological pathways were closely related to ECT through genetic technology analysis, such as LTP pathway and EP300. This study combined with healthy controls and symptomatology analysis to further explore the changes of expression of EP300 protein in treatment and related symptoms of SCZ. Methods: One hundred and one patients with SCZ and 45 healthy controls (HCs) were enrolled in this study. Patients with SCZ received acute courses of 6 times bilateral ECT. The peripheral blood of patients with SCZ (BECT: before ECT; AECT: after ECT) and the HCs was collected to calculate the changes of expression level of EP300 protein by enzyme-linked immunosorbent assay. The Positive and Negative Symptoms Scale (PANSS) was used to evaluate the severity of symptoms of SCZ patients and the efficiency of the ECT. Results: There was a statistical difference of EP300 protein expression in patients with SCZ (BECT and AECT) (F = 114.5, p < 0.05). ECT reduced plasma expression level of EP300 protein in patients with SCZ, which was not statistically different from that in HCs (t = 4.47, p = 0.20). The change of the expression level of EP300 protein in patients with SCZ (BECT and AECT) has a positive correlation with reduction rate of positive symptoms (r = 0.228, p < 0.05) and disturbance of thought (r = 0.219, p < 0.05). Conclusion: Our study suggests that the expression level of EP300 protein has a significant change in patients with SCZ treating with ECT, and EP300 may have some connections with positive symptoms and disturbance thought of patients with SCZ.