ACAP3 negatively regulated by HDAC2 inhibits the malignant development of papillary thyroid carcinoma cells.

ArfGAP with coiled-coil, ankyrin repeat and PH domains 3 (ACAP3) level has been confirmed to be downregulated in papillary thyroid carcinoma (PTC). Histone deacetylase inhibitors (HDACIs) have therapeutic effects on PTC. Accordingly, this study probed into the potential relation of histone deacetylase 2 (HDAC2) and ACAP3 in PTC. Expressions of ACAP3 and HDAC2 in PTC were investigated by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between HDAC2 and ACAP3 was predicted by Pearson analysis. Cell functional assays (cell counting kit-8, transwell, wound healing and flow cytometry assays) and rescue assay were carried out to determine the effects of HDAC2/ACAP3 axis on biological behaviors of PTC cells. Expressions of apoptosis-, epithelial-mesenchymal transition-, Protein Kinase B (AKT)-, and P53-related proteins were measured by Western blot. ACAP3 level was downregulated in PTC tissues and cells. ACAP3 overexpression (oe-ACAP3) suppressed viability, proliferation, migration and invasion of PTC cells, facilitated apoptosis, downregulated the expressions of Protein Kinase B (Bcl-2) and N-cadherin, upregulated the expressions of Bcl-2 associated protein X (Bax) and E-cadherin, diminished the p-AKT/AKT ratio and elevated the p-p53/p53 ratio; however, ACAP3 silencing or HDAC2 overexpression (oe-HDAC2) did the opposite. HDAC2 negatively correlated with ACAP3. The tumor-suppressing effect of oe-ACAP3 in PTC was reversed by oe-HDAC2. Collectively, ACAP3 negatively regulated by HDAC2 suppresses the proliferation and metastasis while facilitating apoptosis of PTC cells.

Identification of potent inhibitors of HDAC2 from herbal products for the treatment of colon cancer: Molecular docking, molecular dynamics simulation, MM/GBSA calculations, DFT studies, and pharmacokinetic analysis.

The histone deacetylase 2 (HDAC2), an enzyme involved in gene regulation, is a potent drug target for the treatment of colon cancer. Phytocompounds having anticancer properties show the ability to interact with HDAC2 enzyme. Among the compounds, docking scores of caffeic acid (CA) and p-coumaric acid (pCA) with HDAC2 showed good binding efficacy of -5.46 kcal/mol and -5.16 kcal/mol, respectively, with small inhibition constants. The higher binding efficacy of CA compared to pCA can be credited to the presence of an extra oxygen atom in the CA molecule, which forms an additional hydrogen bond with Tyr297. The HDAC2 in complex with these molecules was found to be stable by analyzing RMSD, RMSF, Rg, and SASA values obtained through MD simulations. Furthermore, CA and pCA exhibited low MM/GBSA free energies of -16.32 ± 2.62 kcal/mol and -17.01 ± 2.87 kcal/mol, respectively. The HOMO and LUMO energy gaps, dipole moments, global reactivity descriptor values, and MEP surfaces showed the reactivity of the molecules. The favourable physicochemical and pharmacokinetic properties, along with absence of toxicity of the molecules determined using ADMET analysis, suggested both the acids to be regarded as effective drugs in the treatment of colon cancer.

Valproic acid ameliorates cauda equina injury by suppressing HDAC2-mediated ferroptosis.

INTRODUCTION: Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive. METHODS: The cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection. RESULTS: In this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes. CONCLUSION: HDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.

Histone deacetylase inhibitors inhibit lung adenocarcinoma metastasis via HDAC2/YY1 mediated downregulation of Cdh1.

Metastasis is a leading cause of mortality in patients with lung adenocarcinoma. Histone deacetylases have emerged as promising targets for anti-tumor drugs, with histone deacetylase inhibitors (HDACi) being an active area of research. However, the precise mechanisms by which HDACi inhibits lung cancer metastasis remain incompletely understood. In this study, we employed a range of techniques, including qPCR, immunoblotting, co-immunoprecipitation, chromatin-immunoprecipitation, and cell migration assays, in conjunction with online database analysis, to investigate the role of HDACi and HDAC2/YY1 in the process of lung adenocarcinoma migration. The present study has demonstrated that both trichostatin A (TSA) and sodium butyrate (NaBu) significantly inhibit the invasion and migration of lung cancer cells via Histone deacetylase 2 (HDAC2). Overexpression of HDAC2 promotes lung cancer cell migration, whereas shHDAC2 effectively inhibits it. Further investigation revealed that HDAC2 interacts with YY1 and deacetylates Lysine 27 and Lysine9 of Histone 3, thereby inhibiting Cdh1 transcriptional activity and promoting cell migration. These findings have shed light on a novel functional mechanism of HDAC2/YY1 in lung adenocarcinoma cell migration.

HDAC1/2 Control Proliferation and Survival in Adult Epidermis and Pre‒Basal Cell Carcinoma through p16 and p53.

HDAC inhibitors show therapeutic promise for skin malignancies; however, the roles of specific HDACs in adult epidermal homeostasis and in disease are poorly understood. We find that homozygous epidermal codeletion of Hdac1 and Hdac2 in adult mouse epidermis causes reduced basal cell proliferation, apoptosis, inappropriate differentiation, and eventual loss of Hdac1/2-null keratinocytes. Hdac1/2-deficient epidermis displays elevated acetylated p53 and increased expression of the senescence gene p16. Loss of p53 partially restores basal proliferation, whereas p16 deletion promotes long-term survival of Hdac1/2-null keratinocytes. In activated GLI2-driven pre-basal cell carcinoma, Hdac1/2 deletion dramatically reduces proliferation and increases apoptosis, and knockout of either p53 or p16 partially rescues both proliferation and basal cell viability. Topical application of the HDAC inhibitor romidepsin to the normal epidermis or to GLI2ΔN-driven lesions produces similar defects to those caused by genetic Hdac1/2 deletion, and these are partially rescued by loss of p16. These data reveal essential roles for HDAC1/2 in maintaining proliferation and survival of adult epidermal and basal cell carcinoma progenitors and suggest that the efficacy of therapeutic HDAC1/2 inhibition will depend in part on the mutational status of p53 and p16.

A novel HDAC1/2 inhibitor suppresses colorectal cancer through apoptosis induction and cell cycle regulation.

Colorectal cancer (CRC) is one of the leading causes of death around the world, and synthetic chemicals targeting specific proteins or various molecular pathways for tumor suppression, such as histone deacetylases (HADC) inhibitors, are under intensively studied. The target of HDAC involves in regulating critical cellular mechanisms and underpins the progression of anticancer therapy. However, little is known about the antitumor mechanisms of class I specific HDAC inhibitors in CRC. We structurally designed and synthesized benzamide-based compounds, examined their anticancer activity in several solid tumors, and identified compound 9 with high potential. Results from the in vitro enzyme and cell-based studies demonstrated that compound 9 as a selective HDAC1/2 inhibitor that possessed short-term and long-term suppression capacities against colorectal cancer cells. Investigation of molecular regulatory mechanisms of 9 in colorectal cancer cells by biological functional assays evidenced that treatment of compound 9 could activate apoptosis, induce cell cycle arrest, facilitate DNA damage process, and suppress cancer migration. A non-cancerous cell line and the in vivo zebrafish model were applied for safety evaluation. In summary, our results demonstrate that compound 9 is a promising lead drug worth further investigation for development of future cancer therapeutic agents.

Rational design of selective HDAC2 inhibitors for liver cancer treatment: computational insights into the selectivity mechanism through molecular dynamics simulations and QM/MM calculations.

The rational design of selective histone deacetylase 2 (HDAC2) inhibitors is beneficial for the therapeutic treatment of liver cancer, though HDAC2 is highly homologous to HDAC8, which may lead to undesired side effects due to the pan-inhibition towards HDAC2 and HDAC8. To clarify the structural basis of selective inhibition towards HDAC2 over HDAC8, we utilized multiple in silico strategies, including sequence alignment, structural comparison, molecular docking, molecular dynamics simulations, free energy calculations, alanine scanning mutagenesis, pharmacophore modeling, protein contacts atlas analysis and QM/MM calculations to study the binding patterns of HDAC2/8 selective inhibitors. Through the whole process described above, it is found that although HDAC2 has conserved GLY154 and PHE210 that also exist within HDAC8, namely GLY151 and PHE208, the two isoforms exhibit diverse binding modes towards their inhibitors. Typically, HDAC2 inhibitors interact with the Zn2+ ions through the core chelate group, while HDAC8 inhibitors adopt a bent conformation within the HDAC8 pocket that inclines to be in contact with the Zn2+ ions through the terminal hydroxamic acid group. In summary, our data comprehensively elucidate the selectivity mechanism towards HDAC2 over HDAC8, which would guide the rational design of selective HDAC2 inhibitors for liver cancer treatment.

Suppression of Extracellular Vesicle VEGF-C-mediated Lymphangiogenesis and Pancreatic Cancer Early Dissemination By a Selective HDAC1/2 Inhibitor.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by early dissemination and poor drug response. Therefore, it is an unmet medical need to develop new strategies for treatment. As aberrant activation of ERK due to KRAS activating mutation is a driving force for PDAC, a brake system that can terminate ERK signaling represents an ideal druggable target. Herein, we demonstrate that forced expression of dual specificity phosphatase-2 (DUSP2), a specific ERK phosphatase, abrogated tumor formation and loss of Dusp2 facilitated Kras-driven PDAC progression. We report that a selective HDAC1/2 inhibitor (B390) has multifaceted therapeutic potential in PDAC by restoring the expression and function of DUSP2. In vitro study showed that treatment with B390 inhibited growth and migration abilities of PDAC cells, decreased extracellular vesicle-associated VEGF-C expression, and suppressed lymphatic endothelial cell proliferation. In vivo, B390 not only suppressed tumor growth by increasing tumor cell death, it also inhibited lymphangiogenesis and lymphovascular invasion. Taken together, our data demonstrate that B390 was able to alleviate loss of DUSP2-mediated pathologic processes, which provides the proof-of-concept evidence to demonstrate the potential of using selective HDAC1/2 inhibitors in PDAC treatment and suggests reinstating DUSP2 expression may be a strategy to subside PDAC progression.

Histone deacetylase 2 selective inhibitors: A versatile therapeutic strategy as next generation drug target in cancer therapy.

Acetylation and deacetylation of histone and several non-histone proteins are the two important processes amongst the different modes of epigenetic modulation that are involved in regulating cancer initiation and development. Abnormal expression of histone deacetylases (HDACs) is often reported in various types of cancers. Few pan HDAC inhibitors have been approved for use as therapeutic interventions for cancer treatment including vorinostat, belinostat and panobinostat. However, not all the HDAC isoforms are abnormally expressed in certain cancers, such as in the case of, ovarian cancer where overexpression of HDAC1-3, lung cancer where overexpression of HDAC 1 and 3 and gastric cancer where overexpression of HDAC2 is seen. Therefore, pan-inhibition of HDAC is not an efficient way to combat cancer via HDAC inhibition. Hence, isoform-selective HDAC inhibition can be one of the best therapeutic strategies in the treatment of cancer. In this context since aberrant expression of HDAC2 largely contributes to cancer progression by silencing pro-apoptotic protein expressions such as NOXA and APAF1 (caspase 9-activating proteins) and inactivation of tumor suppressor p53, HDAC2 specific inhibitors may help to develop not only the direct targets but also indirect targets that are crucial for tumor development. However, to develop a HDAC2 specific and potent inhibitor, extensive knowledge of its structure and specific functions is essential. The present review updates details on the structural features, physiological functions, and roles of HDAC2 in different types of cancer, emphasizing the challenges and status of the development of HDAC2 selective inhibitors against various types of cancer.

A first-in-class anticancer dual HDAC2/FAK inhibitors bearing hydroxamates/benzamides capped by pyridinyl-1,2,4-triazoles.

Novel 5-pyridinyl-1,2,4-triazoles were designed as dual inhibitors of histone deacetylase 2 (HDAC2) and focal adhesion kinase (FAK). Compounds 5d, 6a, 7c, and 11c were determined as potential inhibitors of both HDAC2 (IC50 = 0.09-1.40 µM) and FAK (IC50 = 12.59-36.11 nM); 6a revealed the highest activity with IC50 values of 0.09 µM and 12.59 nM for HDAC2 and FAK, respectively. Compound 6a was superior to reference drugs vorinostat and valproic acid in its ability to inhibit growth/proliferation of A-498 and Caki-1 renal cancer cells. Further investigation proved that 6a strongly arrests the cell cycle at the G2/M phase and triggers apoptosis in both A-498 and Caki-1 cells. Moreover, the enhanced Akt activity that is observed upon chronic application of HDAC inhibitors was effectively suppressed by the dual HDAC2/FAK inhibitor. Finally, the high potency and selectivity of 6a towards HDAC2 and FAK proteins were rationalized by molecular docking. Taken together, these findings highlight the potential of 6a as a promising dual-acting HDAC2/FAK inhibitor that could benefit from further optimization.

Delineating binding potential, stability of Sulforaphane-N-acetyl-cysteine in the active site of histone deacetylase 2 and testing its cytotoxicity against distinct cancer lines through stringent molecular dynamics, DFT and cell-based assays.

Histone deacetylase 2 (HDAC2), an isozyme of Class I HDACs has potent imputations in actuating neurodegenerative signaling. Currently, there are sizeable therapeutic disquiets with the use of synthetic histone deacetylase inhibitors in disease management. This strongly suggests the unfulfilled medical necessity of plant substitutes for therapeutic intervention. Sulforaphane-N-acetyl-cysteine (SFN-N-acetylcysteine or SFN-NAC), a sulforaphane metabolite has shown significantly worthier activity against HDACs under in vitro conditions. However, the atomistic studies of SFN-NAC against HDAC2 are currently lacking. Thus, the present study employed a hybrid strategy including extra-precision (XP) grid-based flexible molecular docking, molecular mechanics generalized born surface area (MM-GBSA), e-Pharmacophores method, and molecular dynamics simulation for exploring the binding strengh, mode of interaction, e-Pharmacophoric features, and stability of SFN-NAC towards HDAC2. Further, the globally acknowledged density functional theory (DFT) study was performed on SFN-NAC and entinostat individually in complex state with HDAC2. Apart from this, these inhibitors were tested against three distinct cancer cell models and one transformed cell line for cytotoxic activity. Moreover, double mutant of HDAC2 was generated and the binding orientation and interaction of SFN-NAC was scrutinized in this state. On the whole, this study unbosomed and explained the comparatively higher binding affinity of entinostat for HDAC2 and its wide spectrum cytotoxicity than SFN-NAC.

Structure-based virtual screening for novel potential selective inhibitors of class IIa histone deacetylases for cancer treatment.

The fundamental cause of human cancer is strongly influenced by down- or up-regulations of epigenetic factors. Upregulated histone deacetylases (HDAC) have been shown to be effectively neutralized by the action of HDACs inhibitors (HDACi). However, cytotoxicity has been reported in normal cells because of non-specificity of several available HDACis that are in clinical use or at different phases of clinical trials. Because of the high amino acid sequence and structural similarity among HDAC enzymes, it is believed to be a challenging task to obtain isoform-selectivity. The essential aim of the present research work was to identify isoform-selective inhibitors against class IIa HDACs via structure-based drug design. Based on the highest binding affinity and isoform-selectivity, the top-ranked inhibitors were in silico tested for their absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, which were classified as drug-like compounds. Later, molecular dynamics simulation (MD) was carried out for all compound-protein complexes to evaluate the structural stability and the biding mode of the inhibitors, which showed high stability throughout the 100 ns simulation. Free binding energy predictions by MM-PBSA method showed the high binding affinity of the identified compounds toward their respective targets. Hence, these inhibitors could be used as drug candidates or as lead compounds for more in silico or in vitro optimization to design safe isoform-selective HDACs inhibitors.

Histone deacetylase 2: A potential therapeutic target for cancer and neurodegenerative disorders.

Histone deacetylases (HDACs) have been implicated in a number of diseases including cancer, cardiovascular disorders, diabetes mellitus, neurodegenerative disorders and inflammation. For the treatment of epigenetically altered diseases such as cancer, HDAC inhibitors have made a significant progress in terms of development of isoform selective inhibitiors. Isoform specific HDAC inhibitors have less adverse events and better safety profile. A HDAC isoform i.e., HDAC2 demonstrated significant role in the development of variety of diseases, mainly involved in the cancer and neurodegenerative disorders. Discovery and development of selective HDAC2 inhibitors have a great potential for the treatment of target diseases. In the present compilation, we have reviewed the role of HDAC2 in progression of cancer and neurodegenerative disorders, and information on the drug development opportunities for selective HDAC2 inhibition.

Involvement of histone deacetylase 1/2 in adrenocorticotropic hormone synthesis and proliferation of corticotroph tumor AtT-20 cells.

Cushing's disease is mainly caused by autonomous production of adrenocorticotropic hormone (ACTH) from pituitary adenomas. In our previous study, a histone deacetylase (HDAC) inhibitor, trichostatin A, inhibited cell proliferation and ACTH production via decreased pituitary tumor-transforming gene 1 (PTTG1) in AtT-20 mouse corticotroph tumor cells. In the present study, we examined the effects of romidepsin, a potent and selective HDAC1/2 inhibitor, on cell proliferation and ACTH synthesis. To elucidate further potential mechanisms of romidepsin, we examined the effects of HDAC1/2 on proopiomelanocortin (Pomc) and Pttg1 mRNA levels and cell proliferation. Small interfering RNA-mediated knockdown was used to decrease HDAC1 or 2. Romidepsin treatment decreased Pomc and Pttg1 mRNA levels, and cell proliferation. The drug also increased Hdac1 and decreased Hdac2 mRNA levels. Hdac1 knockdown decreased basal Pttg1 mRNA levels and cell proliferation, but not Pomc mRNA levels. Romidepsin treatment decreases ACTH synthesis in corticotroph tumor cells. Romidepsin suppresses cell proliferation via PTTG1. HDAC1 is also involved in the proliferation of corticotroph cells via PTTG1.

Design, synthesis and evaluation of novel indirubin-based N-hydroxybenzamides, N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents.

Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development.

Gallic acid, a phenolic acid, hinders the progression of prostate cancer by inhibition of histone deacetylase 1 and 2 expression.

Gallic acid (GA) is known to possess diverse biological activities, including anticancer. Histone deacetylase (HDACs) are controlled by tumor suppressor gene transcription and are overexpressed in various tumors, resulting in tumor development, progression and poor prognosis. This study aims to demonstrate the effect of GA on inhibition of prostate cancer (PCa) progression by modulating the expression of HDAC1 and 2 in PCa cells. To prove our research rationale, we used diverse experimental methods. GA decreased the cell viability of only PCa cell lines and not normal cells (contrary to another HDAC inhibitor, suberoylanilide hydroxamic acid) and also inhibited colony and tumor spheroid formation. Exposure to GA decreased the mitochondrial membrane potential (ΔΨm), increased the number of apoptotic cells and induced DNA fragmentation. Western blot analysis revealed down-regulated expression of HDAC1 and 2, leading to up-regulation of acetyl-p53 expression at the protein level, subsequent to down-regulating the expression of cell-cycle-related genes, i.e., proliferating cell nuclear antigen (PCNA), Cyclin D1 and E1, up-regulating the expression of cell cycle arrest gene p21 and regulating the expression of apoptosis intrinsic pathway-related genes, such as Bax, Bcl-2, cleaved Caspase-3 and poly (ADP-ribose) polymerase 1 in both PCa cell lines. Furthermore, oral administration of GA for 8 weeks on PC-3 cells-derived tumor xenograft mice model decreases the tumor size, damages the tumor structure and down-regulates the expression of HDAC1 and 2 and PCNA in tumor mass, as confirmed by histological analysis. These results indicated that GA may hinder the PCa progression by inhibiting HDAC1 and 2 expression, thereby demonstrating the potential of GA to be used as HDACs inhibitor and anti-PCa therapeutics.

Histone Deacetylase 2 (HDAC2) Inhibitors Containing Boron.

Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50 =40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50 =42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat (1) toward this particular HDAC isoform.

HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models.

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.

Polysaccharide Nanoparticles Bearing HDAC Inhibitor as Nontoxic Nanocarrier for Drug Delivery.

The histone deacetylase inhibitors (HDACi) are potent drugs in the treatment of inflammatory diseases and defined cancer types. However, major drawbacks of HDACi, such as valproic acid (VPA), are limited serum half-life, side effects and the short circulation time. Thus, the immobilization of VPA in a polysaccharide matrix is used to circumvent these problems and to design a suitable nanocarrier system. Therefore, VPA is covalently attached to cellulose and dextran via esterification with degree of substitution (DS) values of up to 2.20. The resulting hydrophobic polymers are shaped to spherical nanoparticles (NPs) with hydrodynamic diameter between 138 to 221 nm and polydispersity indices from 0.064 to 0.094 by nanoprecipitation and emulsification technique. Lipase treatment of the NPs leads to in vitro release of VPA and hence to an inhibition of HDAC2 activity in a HDAC2 assay. NPs are rapidly taken up by HeLa cells and mainly localize in the cytoplasm. The NPs are hemocompatible and nontoxic as revealed by the shell-less hen's egg model.

Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury.

Nephrotoxicity is a major side effect of cisplatin (CP)- and platinum-related chemotherapy, and inflammation contributes to disease pathogenesis. Interleukin-9 (IL-9) is a pleiotropic cytokine associated with inflammation. Here, we investigated the key role of IL-9 as a regulator of protective mechanisms in CP-induced acute kidney injury (AKI). We observed that IL-9 was decreased not only in a CP-induced AKI mouse model but also in THP-1 and RAW264.7 cell lines. Seventy-two hours post-CP injection, renal dysfunction and tubule injury were significantly attenuated in IL-9 overexpression adeno-associated virus 9 (AAV9)-treated mice. The levels of serum urea, serum creatinine, kidney injury molecule-1 (KIM-1), and histological damage were partially diminished following treatment with IL-9. The renoprotective effects of IL-9 may be attributed to the regulation of cytokines, and we found that IL-9 acted on macrophages in a regulatory manner, promoting an anti-inflammatory phenotype. Furthermore, IL-9 enhanced the suppression of macrophage-driven renal inflammation. Inhibition of H3K27 acetylation orchestrated IL-9-mediated renoprotection in CP-induced AKI. Thus, our findings indicate novel and potent anti-inflammatory properties of IL-9 that confer preservation of kidney function and structure in CP-induced AKI, which may counteract kidney disease procession.