Utilization of an optimized AlphaFold protein model for structure-based design of a selective HDAC11 inhibitor with anti-neuroblastoma activity.

AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 µM on neuroblastoma cells.

Biological function and small molecule inhibitors of histone deacetylase 11.

HDAC11, as a rising star in the histone deacetylase (HDAC) family, has attracted widespread interest in the biomedical field in recent years specially owing to its high defatty-acylase activity compared its innate deacetylase activity. Numerous studies have provided evidence indicating the crucial involvement of HDAC11 in cancers, immune responses, and metabolic processes. Several potent and selective HDAC11 inhibitors have been discovered and identified, which is crucial for exploring the function of HDAC11 and its potential therapeutic applications. Herein, we present a critical overview of the current advances in the biological function of HDAC11 and its inhibitors. We initially discuss the physiological functions of HDAC11 and its pathological roles in relevant diseases. Subsequently, our main focus centers on the design strategy and development process of HDAC11 inhibitors. Additionally, we address significant challenges and outline future directions in this field. This perspective may provide guidance for the further development of HDAC11 inhibitors and their prospects in disease treatment.

Unraveling HDAC11: Epigenetic orchestra in different diseases and structural insights for inhibitor design.

Histone deacetylase 11 (HDAC11), a member of the HDAC family, has emerged as a critical regulator in numerous physiological as well as pathological processes. Due to its diverse roles, HDAC11 has been a focal point of research in recent times. Different non-selective inhibitors are already approved, and research is going on to find selective HDAC11 inhibitors. The objective of this review is to comprehensively explore the role of HDAC11 as a pivotal regulator in a multitude of physiological and pathological processes. It aims to delve into the intricate details of HDAC11's structural and functional aspects, elucidating its molecular interactions and implications in different disease contexts. With a primary focus on elucidating the structure-activity relationships (SARs) of HDAC11 inhibitors, this review also aims to provide a holistic understanding of how its molecular architecture influences its inhibition. Additionally, by integrating both established knowledge and recent research, the review seeks to contribute novel insights into the potential therapeutic applications of HDAC11 inhibitors. Overall, the scope of this review spans from fundamental research elucidating the complexities of HDAC11 biology to the potential of targeting HDAC11 in therapeutic interventions.

Engineering novel scaffolds for specific HDAC11 inhibitors against metabolic diseases exploiting deep learning, virtual screening, and molecular dynamics simulations.

The prevalence of metabolic diseases is increasing at a frightening rate year by year. The burgeoning development of deep learning enables drug design to be more efficient, selective, and structurally novel. The critical relevance of Histone deacetylase 11 (HDAC11) to the pathogenesis of several metabolic diseases makes it a promising drug target for curbing metabolic disorders. The present study aims to design new specific HDAC11 inhibitors for the treatment of metabolic diseases. Deep learning was performed to learn the properties of existing HDAC11 inhibitors and yield a novel compound library containing 23,122 molecules. Subsequently, the compound library was screened by ADMET properties, Lipinski & Veber rules, traditional machine classification models, and molecular docking, and 10 compounds were screened as candidate HDAC11 inhibitors. The stability of the 10 new molecules was further evaluated by deploying RMSD, RMSF, MM/GBSA, free energy landscape mapping, and PCA analysis in molecular dynamics simulations. As a result, ten compounds, Cpd_17556, Cpd_2184, Cpd_8907, Cpd_7771, Cpd_14959, Cpd_7108, Cpd_12383, Cpd_13153, Cpd_14500and Cpd_21811, were characterized as good HDAC11 inhibitors and are expected to be promising drug candidates for metabolic disorders, and further in vitro, in vivo and clinical trials to demonstrate in the future.

HDAC11 Regulates Palmitate-induced NLRP3 Inflammasome Activation by Inducing YAP Expression in THP-1 Cells and PBMCs.

Histone deacetylase 11 (HDAC11) has been implicated in the pathogenesis of metabolic diseases characterized by chronic low-grade inflammation, such as obesity. However, the influence of HDAC11 on inflammation and the specific effect of HDAC11 on the palmitic acid (PA)-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation are poorly understood. The effect of PA treatment on HDAC11 activity and the NLRP3 inflammasome was investigated in human peripheral blood mononuclear cells and THP-1 cells. The PA-induced responses of key markers of NLRP3 inflammasome activation, including NLRP3 gene expression, caspase-1 p10 activation, cleaved IL-1ß production, and extracellular IL-1ß release, were assessed as well. The role of HDAC11 was explored using a specific inhibitor of HDAC11 and by knockdown using small interfering (si)HDAC11 RNA. The relationship between HDAC11 and yes-associated protein (YAP) in the PA-induced NLRP3 inflammasome was investigated in THP-1 cells with HDAC11 or YAP knockdown. Following PA treatment, HDAC11 activity and protein levels increased significantly, concomitant with activation of the NLRP3 inflammasome. Notably, PA-induced the upregulation of NLRP3, caspase-1 p10 activation, the production of cleaved IL-1ß, and the release of IL-1ß into the extracellular space, all of which were attenuated by FT895 treatment and by HDAC11 knockdown. In THP-1 cells, PA induced the expression of YAP and its interaction with NLRP3, resulting in NLRP3 inflammasome activation, whereas both were inhibited by FT895 and siHDAC11 RNA. These findings demonstrate a pivotal role for HDAC11 in the PA-induced activation of the NLRP3 inflammasome. HDAC11 inhibition thus represents a promising therapeutic strategy for mitigating NLRP3 inflammasome-related inflammation in the context of obesity.

Comparative Structure-Based Virtual Screening Utilizing Optimized AlphaFold Model Identifies Selective HDAC11 Inhibitor.

HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold is a machine learning approach that can predict the 3D structure of proteins with high accuracy even in absence of similar structures. However, the fact that AlphaFold models are predicted in the absence of small molecules and ions/cofactors complicates their utilization for drug design. Previously, we optimized an HDAC11 AlphaFold model by adding the catalytic zinc ion and minimization in the presence of reported HDAC11 inhibitors. In the current study, we implement a comparative structure-based virtual screening approach utilizing the previously optimized HDAC11 AlphaFold model to identify novel and selective HDAC11 inhibitors. The stepwise virtual screening approach was successful in identifying a hit that was subsequently tested using an in vitro enzymatic assay. The hit compound showed an IC50 value of 3.5 µM for HDAC11 and could selectively inhibit HDAC11 over other HDAC subtypes at 10 µM concentration. In addition, we carried out molecular dynamics simulations to further confirm the binding hypothesis obtained by the docking study. These results reinforce the previously presented AlphaFold optimization approach and confirm the applicability of AlphaFold models in the search for novel inhibitors for drug discovery.

HDAC11 deficiency resists obesity by converting adipose-derived stem cells into brown adipocyte-like cells.

Obesity, with complications such as type 2 diabetes, dyslipidemia, and even cancer, is rampant worldwide. Histone deacetylases (HDACs) have been extensively studied as key players in the epigenetic regulation of cellular metabolism. However, the function of HDAC11 has long been focused on the immune and nervous systems and cancer development, and its potential role in obesity has been poorly studied. We found that the expression of HDAC11 was highly upregulated in the white adipose tissue (WAT) of obese mice and was closely related to the progression of obesity. Knockdown of HDAC11 by lentiviral injection in high-fat diet-fed mice attenuated the development of obesity. Furthermore, knockdown of HDAC11 ameliorated WAT hypertrophy and induced WAT browning. At the cellular level, silencing of HDAC11 promoted the differentiation of adipose-derived stem cells (ADSCs) into brown adipocyte-like cells and inhibited the proliferation of ADSCs. More interestingly, HDAC11 expression was elevated in ADSCs isolated from obese mice, and silencing of HDAC11 facilitated the spontaneous differentiation of ADSCs into mesoderm, which is the source of adipocytes. This also superficially and effectively demonstrates the exciting prospect of HDAC11 silencing in obesity research and treatment, as a valve for "energy saving and flow reduction".

Utilization of AlphaFold models for drug discovery: Feasibility and challenges. Histone deacetylase 11 as a case study.

Histone deacetylase 11 (HDAC11), an enzyme that cleaves acyl groups from acylated lysine residues, is the sole member of class IV of HDAC family with no reported crystal structure so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms which complicates the conventional template-based homology modeling. AlphaFold is a neural network machine learning approach for predicting the 3D structures of proteins with atomic accuracy even in absence of similar structures. However, the structures predicted by AlphaFold are missing small molecules as ligands and cofactors. In our study, we first optimized the HDAC11 AlphaFold model by adding the catalytic zinc ion followed by assessment of the usability of the model by docking of the selective inhibitor FT895. Minimization of the optimized model in presence of transplanted inhibitors, which have been described as HDAC11 inhibitors, was performed. Four complexes were generated and proved to be stable using three replicas of 50 ns MD simulations and were successfully utilized for docking of the selective inhibitors FT895, MIR002 and SIS17. For SIS17, The most reasonable pose was selected based on structural comparison between HDAC6, HDAC8 and the HDAC11 optimized AlphaFold model. The manually optimized HDAC11 model is thus able to explain the binding behavior of known HDAC11 inhibitors and can be used for further structure-based optimization.

HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285.

Cytarabine-resistant acute myeloid leukemia (AML) is a common phenomenon, necessitating the search for new chemotherapeutics. WEE1 participates in cell cycle checkpoint signaling and inhibitors targeting WEE1 (WEE1i) constitute a potential novel strategy for AML treatment. HDAC (histone deacetylase) inhibitors have been shown to enhance the anti-tumor effects of WEE1i but molecular mechanisms of HDAC remain poorly characterized. In this study, the WEE1 inhibitor PD0166285 showed a relatively good anti-leukemia effect. Notably, PD0166285 can arise the expression of HDAC11 which was negatively correlated with survival of AML patients. Moreover, HDAC11 can reduced the anti-tumor effect of PD0166285 through an effect on p53 stability and the changes in phosphorylation levels of MAPK pathways. Overall, the cell cycle inhibitor, PD0166285, is a potential chemotherapeutic drug for AML. These fundings contribute to a functional understanding of HDAC11 in AML.

HDAC11: A novel target for improved cancer therapy.

Histone deacetylase 11 (HDAC11) is a unique member of the histone deacetylase family that plays an important role in the regulation of gene expression and protein function. In recent years, research on the role of HDAC11 in tumors has attracted increasing attention. This review summarizes the current knowledge on the subcellular localization, structure, expression, and functions of HDAC11 in tumors, as well as the regulatory mechanisms involved in its network, including ncRNA and substrates. Moreover, we focus on the progress made in targeting HDAC11 to overcome tumor therapy resistance, and the development of HDAC11 inhibitors for cancer treatment. Collectively, this review provides comprehensive insights into the potential clinical implications of HDAC11 for cancer therapy.

Identification of potential HDAC11 deacylase substrates by affinity pulldown MS.

Lysine fatty acylation is a protein posttranslational modification (PTM) that has been linked to various important biological processes. HDAC11, the sole member of class IV of histone deacetylases (HDACs), has been shown to have high lysine defatty-acylase activity. In order to better understand the functions of lysine fatty acylation and its regulation by HDAC11, it is important to identify the physiological substrates of HDAC11. This can be achieved through profiling the interactome of HDAC11 using a stable isotope labeling with amino acids in cell culture (SILAC) proteomics strategy. Here we describe a detailed method on using SILAC to identify the interactome of HDAC11. This method can be similarly used to identify the interactome, and thus potential substrates, of other PTM enzymes.

Targeting HDAC11 activity by FT895 restricts EV71 replication.

Enterovirus 71 (EV71) infection mainly causes hand, foot, and mouth disease (HFMD) and remains a serious public health problem to the children under the age of 5. Until now, there is no specific drug to treat HFMD in clinical and there is an urgent to explore the new target and the new drug to address clinical challenges. At present, we found histone deacetylase 11 (HDAC11) involves in supporting EV71 replication. We also used HDAC11 siRNA and an HDAC11 inhibitor FT895 to downregulate HDAC11 expression and found that targeting HDAC11 could significantly restrict EV71 replication in vitro and in vivo. Our results revealed the new role of HDAC11 participating in EV71 replication and broadened our knowledge regarding the functions of HDAC11 and the roles of HDACs in the epigenetic regulation of viral infectious diseases. Our results for the first time identified FT895 as an effective inhibitor of EV71 in vitro and in vivo, which may contribute to be a potential drug to treat HFMD.

HDAC11, an emerging therapeutic target for metabolic disorders.

Histone deacetylase 11 (HDAC11) is the only member of the class IV HDAC, and the latest member identified. It is highly expressed in brain, heart, kidney and some other organs, and located in mitochondria, cytoplasm and nuclei, depending on the tissue and cell types. Although studies in HDAC11 total knockout mice suggest its dispensable features for tissue development and life, it participates in diverse pathophysiological processes, such as DNA replication, tumor growth, immune regulation, oxidant stress injury and neurological function of cocaine. Recent studies have shown that HDAC11 is also critically involved in the pathogenesis of some metabolic diseases, including obesity, diabetes and complications of diabetes. In this review, we summarize the recent progress on the role and mechanism of HDAC11 in the regulation of metabolic disorders, with the focus on its regulation on adipogenesis, lipid metabolism, metabolic inflammation, glucose tolerance, immune responses and energy consumption. We also discuss the property and selectivity of HDAC11 inhibitors and their applications in a variety of in vitro and in vivo models of metabolic disorders. Given that pharmacological and genetic inhibition of HDAC11 exerts a beneficial effect on various metabolic disorders, HDAC11 may be a potential therapeutic target to treat chronic metabolic diseases.

Overexpression of NR4A2 alleviates renal and myocardial injury in diabetes nephropathy rats through the HDAC11/SPRY1 pathway.

BACKGROUND: Diabetic nephropathy (DN) remains the most prevalent cause of end-stage renal disease. Nuclear receptor subfamily 4 group A member 2 (NR4A2) is a nuclear receptor with unique physiological characteristics. OBJECTIVE: This study explored the molecular mechanism of NR4A2 in renal and cardiac functions of DN rats. METHODS: A rat model of DN was established by intraperitoneal injection of streptozocin. NR4A2, histone deacetylase 11 (HDAC11), and sprouty 1 (SPRY1) expressions were detected. The fasting blood glucose (FBG), urinary albumin (UAlb), serum creatinine (Cr), and blood urea nitrogen (BUN) were determined. The pathological injury of renal and myocardial tissues was evaluated. The mitral early to late diastolic flow velocity ratio (E/A ratio), left ventricular ejection fraction (LVEF), left ventricular systolic function (LVSF), left ventricular internal dimension systole (LVIDs), and left ventricular internal diameter diastole (LVIDd) were tested, and the levels of serum cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) were examined. The enrichment of NR4A2 in HDAC11 promoter and enrichment of H3K27 acetylation in SPRY1 promoter were measured. RESULTS: NR4A2 and SPRY1 were downregulated while HDAC11 was upregulated in renal and myocardial tissues of DN rats. NR4A2 overexpression reduced FBG, UAlb, Cr, and BUN, alleviated pathological injury of renal and myocardial tissues, elevated the E/A ratio, LVEF, and LVFS, but reduced LVIDs, and decreased serum cTnI and CK-MB. NR4A2 depressed HDAC11 expression by binding to the HDAC11 promoter. HDAC11 repressed SPRY1 transcription by suppressing the H3K27ac level. HDAC11 overexpression or SPRY1 inhibition reversed the alleviating effect of NR4A2 overexpression on DN rats. CONCLUSION: NR4A2 was poorly expressed in DN rats. NR4A2 overexpression suppressed HDAC11 expression by binding to the HDAC11 promoter and enhanced SPRY1 transcription by enhancing H3K27 acetylation, thereby alleviating the renal and myocardial injury of DN rats.

LncRNA C9orf139 can regulate the progression of esophageal squamous carcinoma by mediating the miR-661/HDAC11 axis.

Increasing evidence has indicated that long non-coding RNAs (LncRNAs) play multiple functions in the development of cancer and function as indicators of diagnosis and prognosis. This aim of this study was to investigate the roles LncRNA C9orF139 had in the progression of esophageal squamous carcinoma (ESCC). We found C9orf139 was highly expressed in ESCC and knock down the expression of C9orf139 significantly suppressed cell proliferation, promoted apoptosis, and inhibited migration and invasion. C9orf139 was able to negatively regulate miR-661 expression. At the same time, HDAC11 expression was negatively regulated by miR-661. The C9orf139/miR-661/HDAC11 axis was further involved in regulating the expression of the NF-κB signaling pathway. The association between the C9orf139 knockdown and the reduced tumor growth and size was observed during in vivo study. C9orf139 is highly expressed in ESCC, and is thus qualified to be used as a potential diagnostic and prognostic marker for ESCC. Its promotion of ESCC progression is achieved by mediating the miR-661/HDAC11 axis.

HDAC11 Regulates the Proliferation of Bovine Muscle Stem Cells through the Notch Signaling Pathway and Inhibits Muscle Regeneration.

Myogenesis is an essential process that can affect the yield and quality of beef. Transcriptional studies have shown that histone deacetylase 11 (HDAC11) was differentially expressed in muscle tissues of 6 and 18 month old Longlin cattle, but its role in the regulation of myogenesis remains unclear. This study aimed to determine the role of HDAC11 in the proliferation and differentiation of bovine muscle stem cells (MuSCs). HDAC11 promoted MuSC proliferation by activating Notch signaling and inhibited myoblast differentiation by reducing MyoD1 transcription. In addition, overexpression of HDAC11 inhibited the repair regeneration process of muscle in mice. HDAC11 was found to be a novel key target for the control of myogenesis, and this is a theoretical basis for the development of HDAC11-specific modulators as a new strategy to regulate myogenesis.

Clinicopathological characteristics and prognostic significance of HDAC11 protein expression in non-small cell lung cancer: a retrospective study.

Background: Although the prognosis of non-small cell lung cancer (NSCLC) can be assessed based on pathological type, disease stage and inflammatory indicators, the prognostic scoring model of NSCLC still needs to improve. HDAC11 is associated with poor prognosis of partial tumors, but its prognostic relationship with NSCLC is poorly understood. In this study, the role of HDAC11 in NSCLC was studied to evaluate relationship with disease prognosis and potential therapeutic target. Methods: The clinicopathological and paracancerous tissues of patients with NSCLC primarily diagnosed in Tangdu Hospital from 2009 to 2013 were collected. Follow-up of patients were made every three months and the last follow-up period was December 2018. The expression of HDAC11 was assessed by immunohistochemistry (IHC). Then, weighted gene co-expression network analysis (WGCNA) was used to analyze the relationship between HDAC11 expression and the prognosis of lung adenocarcinoma (LUAD) patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Kaplan-Meier plotter database was used to verify the connection between hub genes and tumor stage and prognosis. We accessed the relationship between HDAC11 expression and clinicopathological features, and impact on the prognosis. Results: The study assessed 326 patients with NSCLC. Compared with adjacent tissues, HDAC11 expression was upregulated (HR =1.503, 95% CI: 1.172 to 1.927, P=0.001). Kaplan-Meier survival analyses showed that HDAC11 expression was closely related to OS of NSCLC patients (P=0.0011). Univariate and multivariate analyses showed that the independent risk factors of OS were clinical stage, HDAC11 expression, and HDAC11 differentiation (all P≤0.001). HDAC11 was significantly associated with prognosis in LUAD. A total of 1,174 differential genes and WGCNA were obtained to construct a co-expression network in LUAD. The GO and KEGG pathway enrichment analyses showed the relevance with staphylococcus aureus infection, NOD-like receptor signaling pathway, and others. The results of LUAD survival analysis showed that HDAC11-related genes NKX2-5 and FABP7 were significantly associated with LUAD prognosis. Conclusions: The high expression of HDAC11 is related to the poor prognosis of LUAD, and it is expected to become a therapeutic target and prognostic evaluation therapy for LUAD in the future. However, the relevant results need to be further studied and verified.

A pan-cancer analysis identifies HDAC11 as an immunological and prognostic biomarker.

Histone deacetylase 11 (HDAC11) is aberrantly expressed in many types of cancer, and such abnormalities are associated with tumor immunity and heterogeneous clinical outcomes. Here, we explore the prognostic value and immunological function of HDAC11 across 33 cancer types. We observe HDAC11 is aberrantly expressed in 25 cancer types and positively or negatively associated with prognosis in different cancers. HDAC11 played a protective prognostic role in KIRP, KIRC, LGG, PCPG, READ, and UVM, which was contrary to the conventional opinion that HDAC11 was an oncogenic gene. Moreover, HDAC11 is negatively associated with tumor immune components, most immune checkpoint genes, and key cytokine expression. HDAC11 is correlated with tumor mutational burden in 11 cancer types and with microsatellite instability in 9 cancer types, suggesting HDAC11 may affect a patient's response to immune checkpoint inhibitor (ICI) therapy. In addition, HDAC11 is negatively correlated with the drug sensitivity of oxaliplatin, carmustine, ifosfamide, imexon, lomustine, and BN-2629, indicating the potential synergy between HDAC11 inhibitors and these anti-tumor drugs. In vitro assays indicate that HDAC11 inhibitor SIS17 combined with oxaliplatin shows a synergistic cytotoxic role in K562 cells while SIS17 has an antagonistic effect on the cytotoxic role of oxaliplatin in 769P cells. HDAC11 is also associated with hallmark pathways, including epithelial mesenchymal transition, IL-6/JAK/STAT3, and allograft rejection pathways. Overall, we provide clues regarding the key role of HDAC11 in multiple cancers.

Histone deacetylase (HDAC) 11 inhibits matrix metalloproteinase (MMP) 3 expression to suppress colorectal cancer metastasis.

Emerging evidence has implicated invasion and metastasis are the major common reason of treatment failure and the leading cause of death in colorectal cancer (CRC). Many members of the HDAC family have been reported to be key factors in the genesis and progression of cancer. Until now, few research focused on the actual expression patterns of HDAC11 in most malignancies. In the current study, we found that the expression of HDAC11 is decreased in mouse colitis tissues and colitis-associated cancer (CAC) tissue compared with normal colon tissue. Clinically HDAC11 expression is significantly lower in colorectal cancer tissues of patients and correlated with lymph node metastasis. Additionally, HDAC11 is downregulated in the relative high metastatic potential colorectal cancer cells. We also found HDAC11 inhibits the migration and invasion of colorectal cancer cell by downregulating Mmp3 expression. At the molecular level, the expression of HDAC11 inversely correlated with the level of histone H3K9 and H3K14 acetylation. In addition, analysis of chromatin-protein association by ChIP-qPCR demonstrated that the level of H3K9 acetylation correlated with the upregulation of Mmp3. Through a better understanding of this previously unknown role of HDAC11 in migration and invasion of colorectal cancer, HDAC11 may become a novel candidate for developing rational therapeutic strategies.

A novel HDAC11 inhibitor potentiates the tumoricidal effects of cordycepin against malignant peripheral nerve sheath tumor through the Hippo signaling pathway.

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder. Clinically, the hallmarks of NF1 include skin pigmentation and cutaneous neurofibroma. Some NF1 patients develop plexiform neurofibroma (PN) since early childhood. Pathologically, PN contains abundant Schwann cells, blood vessels and connective tissues, which may transform into a malignant peripheral nerve sheath tumor (MPNST). MPNST is a highly invasive sarcoma without any effective therapy. Recently, both in vitro and in vivo studies showed that cordycepin can inhibit the growth of MPNST cells. Cordycepin causes cell cycle arrest at G2/M phase and downregulates the protein levels of α-tubulin, p53 and Sp1. Herein, the present study revealed that the HDAC11 inhibitor, FT895, can synergistically enhance the tumoricidal effect of cordycepin against MPNST cells in vitro. Treatment with the combination of cordycepin and FT895 reduced the size of MPNST in the xenograft mouse model. The combined treatment decreased the protein levels of α-tubulin and KIF18A, which may disrupt the microtubule organization leading to the mis-segregation of chromosomes and aneuploidy. Moreover, the expression levels of TEAD1 and its co-activator TAZ, the candidate proteins in hippo signaling pathway, were suppressed after combined treatment. Sequence analysis found a few binding sites for the transcription factor, TEAD1 in the promoter regions of TUBA1B, KIF18A, TEAD1, TAZ, YAP, TP53 and SP1 genes. ChIP-qPCR assay showed that the combined treatment decreases the binding of TEAD1 to the promoters of TUBA1B, KIF18A, TEAD1, TAZ and YAP genes in STS26T cells. The reduced binding to TP53 and SP1 promoters was also found in S462TY cells, which was further confirmed by immunoblotting. The down-regulation of these important transcriptional factors may contribute to the vulnerability of MPNST. In summary, HDAC11 inhibitor, FT895 can potentiate the tumoricidal effect of cordycepin to suppress the MPNST cell growth, which was probably mediated by the dysfunction of hippo-signaling pathway.