Overexpression Of Histone Deacetylases Research Articles

Exploration of novel hydroxamate zinc binding group inhibitors against HDAC-1-3 enzymes by AI-based virtual screening: atomistic insights from steered molecular dynamics

Overexpression of histone deacetylase (HDAC) enzymes is linked to a wide variety of illnesses, including malignancies and neurological disorders, which makes HDAC inhibitors potentially therapeutic. However, most HDAC inhibitors lack subclass or isoform selectivity, which can be dangerous. Featuring both enhanced selectivity and toxicity profiles, slow-binding HDAC inhibitors offer promising treatment options for a variety of disorders. Diseases like cardiac, neurodegenerative disorders and diabetes are mainly associated with the HDAC1, HDAC2 and HDAC3 enzymes. The AI-based virtual screening tool PyRMD is implemented to identify the potential inhibitors from ∼2 million compounds. Based on the IC50 values, the top 10 compounds were selected for molecular docking. From the docking and ADMET study, the top-ranked three compounds were selected for molecular dynamics (MD) simulations. Further, to get more insights into the binding/unbinding mechanism of the ligand, we have employed the steered molecular dynamics (SMD) simulations. This study assists in developing Amber force field parameters for the HDAC1, HDAC2 and HDAC3 proteins and sheds light on the discovery of a potent drug. Our study suggests that hydroxamic acid derivative (i.e. referred to as Comp-1, CHEMBL600072) is the potential inhibitor for the series of HDAC-related diseases. Communicated by Ramaswamy H. Sarma

HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease.

Vascular calcification is a major risk factor for cardiovascular disease mortality, with a significant prevalence in chronic kidney disease (CKD). Pharmacological inhibition of histone acetyltransferase has been proven to protect against from vascular calcification. However, the role of Histone Deacetylase 2 (HDAC2) and molecular mechanisms in vascular calcification of CKD remains unknown. An invivo model of CKD was established using mouse fed with a high adenine and phosphate diet, and an invitro model was produced using human aortic vascular smooth muscle cells (VSMCs) stimulated with β-glycerophosphate (β-GP). HDAC2 expression was found to be reduced in medial artery of CKD mice and β-GP-induced VSMCs. Overexpression of HDAC2 attenuated OPN and OCN upregulation, α-SMA and SM22α downregulation, and calcium deposition in aortas of CKD. The invitro results also demonstrated that β-GP-induced osteogenic differentiation was inhibited by HDAC2. Furthermore, we found that HDAC2 overexpression caused an increase in LC3II/I, a decrease in p62, and an induction of autophagic flux. Inhibition of autophagy using its specific inhibitor 3-MA blocked HDAC2's protective effect on osteogenic differentiation in β-GP-treated VSMCs. Taken together, these results suggest that HDAC2 may protect against vascular calcification by the activation of autophagy, laying out a novel insight for the molecular mechanism in vascular calcification of CKD.

Histone Deacetylase 2 Stabilizes SPARC-related Modular Calcium Binding 2 to Promote Metastasis and Stemness in Gallbladder Cancer.

We aimed to investigate the relationship between histone deacetylase 2 (HDAC2) and SPARC-related modular calcium binding 2 (SMOC2) and the role of SMOC2 in gallbladder cancer (GBC). The expression of HDAC2 and SMOC2 in GBC and normal cells was detected by quantitative real-time reverse transcription polymerase chain reaction (qRTPCR), which was also used to detect the mRNA stability of SMOC2. The combination between HDAC2 and SMOC2 was detected by Chromatin immunoprecipitation (ChIP) assay. After silencing and/or overexpressing HDAC2 and SMOC2, cell viability, migration, invasion, and stemness were respectively tested by the Cell Counting Kit-8 (CCK-8), cell scratch, transwell, and sphere-formation assay. In GBC cells, HDAC2 and SMOC2 were highly expressed. HDAC2 combined with SMOC2 promoted mRNA stability of SMOC2. HDAC2 or SMOC2 overexpression promoted GBC cell metastasis and stemness. SMOC2 overexpression rescued the negative effects of silencing HDAC2 in GBC. HDAC2 stabilizes SMOC2 to promote metastasis and stemness in gallbladder cancer.

Evaluation of the Histone Deacetylase 2 (HDAC-2) Expression in Human Breast Cancer.

Triple negative breast cancer belongs to the most aggressive breast cancer forms. Histone deacetylases (HDACs) constitute a class of enzymes that exhibit a significant role in breast cancer genesis and progression. In this study, we aimed at assessing the clinical importance of HDAC-2 in triple negative breast cancer. A total of 138 breast cancer specimens were examined on an immunohistochemical basis. A statistical analysis was performed in order to examine the association between HDAC-2 and the survival and clinicopathological features of the patients. Increased HDAC-2 expression was observed in every fourth case of triple negative breast cancer with positive HDAC-2 staining, whereas only 12 out of 98 non-triple negative breast cancer samples showed high HDAC-2 expression. HDAC-2 overexpression correlated with prolonged overall survival (OS) and disease-free survival (DFS) in triple negative breast cancer. High HDAC-2 levels in triple negative breast cancer seem to positively influence patient survival, disease stage and recurrence.

Relationship between Histone Deacetylase (HDAC) Overexpression and 18F-FDG PET/CT Parameters in Patients with Gastric Cancer, and Prognostic Importance of HDAC Overexpression

Ozge Ulas BABACAN1, Zekiye HASBEK2, Mukaddes YILMAZ3, Hatice OZER4, Hilmi ATASEVEN5 1Bitlis State Hospital, Department of Nuclear Medicine, Bitlis 2Cumhuriyet University Faculty of Medicine, Department of Nuclear Medicine 3Cumhuriyet University Faculty of Medicine, Department of Oncology 4Cumhuriyet University Faculty of Medicine, Department of Pathology 5Cumhuriyet University Faculty of Medicine, Department of Gastroenterology Keywords: HDAC, HDACI, 18F-FDG PET/CT, Gastric cancer Histon Deacetylases (HDACs) exert a pro-oncogenic effect by keeping genes that cause differentiation, apoptosis, and cell cycle arrest in a transcriptionally quiescent state. Moreover to achieve our aim, we investigated the relationship between the patients’ HDAC protein expression rates and their prognosis. In no patients, tumors were located in the cardia and corpus. While the median HDAC1 protein score was 3.5 in the early stage patients, it was 8 in the advanced stage (stage 1-2) patients, and 12 in the metastatic stage (stage 4) patients. There was a significant correlation between HDAC protein positivity and tumor localization (p= 0.030). Significant correlation was observed between histopathological stages and median HDAC1 protein scores. (p= 0.021). The HDAC1 protein score increased as the patients’ stage progressed. Given the relationship between HDAC1 proteins and the survival of the patients, the 2-year survival rate was high in HDAC1 positive patients; however, it was not statistically significant. According to the results of our study, in HDAC1-positive gastric cancer patients, there was no significant relationship between SUVmax showing tumor metabolism in 18F-FDG PET/CT.

Abstract A037: Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2

Abstract Background: Treatment-related neuroendocrine prostate cancer (NEPC) is an aggressive subset of castration-resistant prostate cancer (CRPC), found in ~20% of lethal CRPC. The mechanisms underlying the progression of prostate cancer to NEPC are largely unclear, and new drug targets are desperately needed. NEPC is known to be highly vascularized. Elevated expression of NE markers and increased angiogenesis are two prominent phenotypes of NEPC, and thus are expected to be linked. However, direct molecular links between these two phenotypes are still elusive, whose elucidation will substantially expand our knowledge in NEPC and enable the development of effective treatments for NEPC. Through RNAi & cDNA screening and functional validations, we previously discovered that GPCR-kinase 3 (GRK3) is essential preferentially for highly metastatic cancer cells as compared to lowly metastatic cancer cells. The mechanisms of GRK3 in prostate cancer progression were mostly unknown. Methods: We assessed GRK3’s expression in patient samples through IHC staining on TMA and data mining on public RNA-seq datasets with large cohorts. Using molecular and cell biology methods, we determined the impacts of GRK3 and HDAC2 overexpression and silencing on NE marker expression and angiogenesis in prostate cancer cells. Through biochemistry, we investigated the nature of GRK3-HDAC2 relation. By ChIP-PCR, we measured the impacts of GRK3 genetic and pharmacological modulations on HDAC2’s epigenetic activity. Through compound library screening and biochemical characterization, we searched for novel GRK3 inhibitors to study GRK3 biology and to evaluate whether GRK3 is a suitable drug target for prostate cancer. Results: GRK3 is significantly overexpressed in metastatic prostate tumors from patients, especially in NEPC. GRK3 promotes both angiogenesis and neuroendocrine differentiation in prostate cancer cells, indicating that it is a key missing link for these two phenotypes. Mechanistically, GRK3 enhances the epigenetic repressor activity of histone deacetylase 2 (HDAC2) to suppress key repressors of angiogenesis or NE phenotype. We have identified several compounds that block kinase activity of GRK3 much more potently than that of GRK2, the closest-related kinase to GRK3. Of note, our GRK3 inhibitors could substantially reduce angiogenesis and NE marker expression, as well as significantly inhibit NEPC cell growth in culture and in mouse xenografts. Conclusion: Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression. Its mechanism of actions is at least in part through enhancing HDAC2’s epigenetic activity. Results based on our novel GRK3 inhibitors suggest that GRK3 is a valuable new drug target for aggressive prostate cancer. Citation Format: Samira Naderinezhad, Zheng Wang, Guoliang Zhang, Michael Ittmann, Martin Gleave, Wenliang Li. Kinase GRK3 connects angiogenesis and neuroendocrine differentiation in prostate cancer progression by enhancing epigenetic activity of HDAC2 [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A037.

Abstract A059: Epigenetic remodelling by class I HDAC inhibitors increases response to androgen signalling inhibitors in prostate cancer

Abstract Prostate cancer (PCa) is one of the most prevalent cancers in the male population with approximately 1 in 8 men diagnosed with the disease during their lifetime. The treatment options available varies depending on individual circumstances, with surgery or radiotherapy employed as first-line treatments for locally advanced PCa whilst hormone therapies are employed as the disease progresses toward castrate-resistant prostate cancer. Despite the advances in therapies and initial treatment effectiveness, tumours develop resistance and overcoming this resistance proves a major challenge for the treatment of the disease. Dysregulation of chromatin regulatory proteins and the epigenetic landscape are key factors contributing to the development, progression and persistence of PCa. Histone deacetylases (HDACs) are a family of chromatin-modifying proteins which assemble into various transcriptional repressor complexes and mediate gene repression through the removal of acetyl groups from histone tails, subsequently compacting the chromatin landscape impacting on cell proliferation, transcription, replication and DNA repair. Overexpression of HDACs in prostate cancer has been shown to shift the balance of acetylation, resulting in improper gene silencing. Therefore, we hypothesise that restoration of the acetylation homeostasis through HDAC inhibition is a potential therapy to overcome resistance in PCa. Here, we show that the class I HDAC inhibitor Entinostat as a single agent promotes anti-tumour effects in PCa by impairing cell proliferation and inducing apoptosis in a panel of PCa cell lines. Interestingly, we found that combination with the androgen signalling inhibitors (ASIs), Enzalutamide or Abiraterone, further enhances these anti-tumour effects. In vitro analysis of matched parental and Enzalutamide-/Abiraterone-resistant C4-2B and CWRR-1 cells further revealed an enhanced reduction in cell survival following combined Entinostat and ASIs treatments in the resistant models compared to parental. Genomic and transcriptomic analyses uncovered distinct molecular signatures of these resistant models. Treatment with Entinostat alone downregulated androgen receptor (AR) expression and combination with ASI further suppressed AR expression and downstream AR target genes. Taken together, these results demonstrate the potential for Entinostat to synergise with current standard-of-care therapies to target ASI resistance in PCa. In conclusion, this study provides strong evidence suggesting the effectiveness of class I HDAC inhibition by Entinostat in the treatment of castration-resistant prostate cancer and opens the door for further research into combinatorial therapies in targeting resistance. Citation Format: Rachel McCole, Ben McCullough, Judith M. Manley, Nicholas Forsythe, Simon S. McDade, Melissa LaBonte Wilson. Epigenetic remodelling by class I HDAC inhibitors increases response to androgen signalling inhibitors in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A059.

Cell-of-Origin Targeted Drug Repurposing for Triple-Negative and Inflammatory Breast Carcinoma with HDAC and HSP90 Inhibitors Combined with Niclosamide.

We recently identified a cell-of-origin-specific mRNA signature associated with metastasis and poor outcome in triple-negative carcinoma (TNBC). This TNBC cell-of-origin signature is associated with the over-expression of histone deacetylases and zinc finger protein HDAC1, HDAC7, and ZNF92, respectively. Based on this signature, we discovered that the combination of three drugs (an HDAC inhibitor, an anti-helminthic Niclosamide, and an antibiotic Tanespimycin that inhibits HSP90) synergistically reduces the proliferation of the twelve tested TNBC cell lines. Additionally, we discovered that four out of five inflammatory breast carcinoma cell lines are sensitive to this combination. Significantly, the concentration of the drugs that are used in these experiments are within or below clinically achievable dose, and the synergistic activity only emerged when all three drugs were combined. Our results suggest that HDAC and HSP90 inhibitors combined with the tapeworm drug Niclosamide can achieve remarkably synergistic inhibition of TNBC and IBC. Since Niclosamide, HDAC, and HSP90 inhibitors were approved for clinical use for other cancer types, it may be possible to repurpose their combination for TNBC and IBC.

Modificações epigenéticas de histonas e sua relação com o câncer: uma visão da medicina comparada

ABSTRACT: Epigenetic modifications have become highly important in the study of cancer pathogenesis due to research showing that changes in the expression of DNA-associated proteins can affect gene expression but may be reversible after treatment. The changing histones are being studied on a large scale in medicine while recent studies also show this relationship in veterinary medicine. Histone deacetylation is related to tumor progression and overexpression of histone deacetylases (HDACs) is responsible for these changes. The silencing of tumor suppressor genes related to epigenetic changes favors tumor progression; however, using HDAC inhibitors has been shown to effectively reverse these histone changes while having anticancer effects. This research provided an overview of comparative medicine between humans and dogs concerning epigenetic changes while showing the physiological mechanisms and the relationship between cancer and epigenetics, specifically regarding histone acetylation and deacetylation. This overview should contribute to a better understanding of epigenetics and cancer and their relationship with new target-molecular therapies in veterinary medicine and the importance of such studies.

HDAC6, une désacétylase très spécifique porteuse d’espoir thérapeutique

The cytoplasmic histone deacetylase 6 (HDAC6) is defined today as a new key player in the treatment of many diseases. Overexpression of HDAC6 was observed in a variety of diseases. Over the past ten years, plenty of new selective inhibitors of HDAC6 activity have been synthesized and characterized. Many studies have shown the high efficiency and beneficial effects of HDAC6 inhibitors in many diseases such as cancers, neurodegenerative, inflammatory, or neuromuscular diseases. The mechanisms of HDAC6 action that explain the benefit of its inhibition in various pathologies are still unknown. We have recently shown that HDAC6, via the regulation of the microtubule network, plays a role at the level of neuromuscular junctions by controlling acetylcholine receptor delivery.

Single and repeated bisphenol A treatment induces ROS, Aβ and hyperphosphorylated-tau accumulation, and insulin pathways disruption, through HDAC2 and PTP1B overexpression, leading to SN56 cholinergic apoptotic cell death.

Bisphenol-A (BPA), a polymer component extensively used, produces memory and learning alterations after acute and long-term exposure. However, the mechanisms are not well known. Cortex and hippocampus neuronal networks control cognitive functions, which are innervated by basal forebrain cholinergic neurons (BFCN), and their neurodegeneration induces cognitive dysfunctions. Wild type or protein tyrosine phosphatase 1B (PTP1B), histone deacetylase 2 (HDAC2), tau or β amyloid precursor protein (βAPP) silenced SN56cells treated with BPA (0.001μM-100μM) with or without N-acetylcysteine (NAC; 1mM), following 1 and 14 days, were used, as a model of BFCN to determine the insulin pathway dysfunction, oxidative stress (OS) generation and amyloid-β (Aβ) and tau proteins accumulation involvement in the BCFN cell death induction, as a possible mechanism that could produce the cognitive disorders reported. BPA-induced BFCN cell death, after 24h and 14 days of treatment, through insulin pathway dysfunction, OS generation, mediated by NRF2 pathway downregulation, and Aβ and tau proteins accumulation, which were in turn induced by HDAC2 and PTP1B overexpression. This is relevant information to explain the BFCN neurodegeneration mechanisms that could trigger the neurodegeneration in the rest of the regions innerved by them, leading to cognitive disorders.

A bionic multichannel nanofiber conduit carrying Tubastatin A for repairing injured spinal cord.

Spinal cord injury is a kind of nerve injury disease with high disability rate. The bioscaffold, which presents a biomimetic structure, can be used as “bridge” to fill the cavity formed by the liquefaction and necrosis of spinal nerve cells, and connects the two ends of the fracture to promote the effective recovery of nerve function. Tubasatin A (TUBA) is a potent selective histone deacetylase 6 (HDAC6) inhibitor, which can inhibit the overexpression of HDAC6 after spinal cord injury. However, TUBA is limited by high efflux ratios, low brain penetration and uptake in the treatment of spinal cord injury. Therefore, an effective carrier with efficient load rate, sustained drug release profile, and prominent repair effect is urgent to be developed. In this study, we have prepared a bionic multichannel Tubasatin A loaded nanofiber conduit (SC-TUBA(+)) through random electrospinning and post-triple network bond crosslinking for inhibiting HDAC6 as well as promoting axonal regeneration during spinal cord injury treatment. The Tubasatin A-loaded nanofibers were shown to be successfully contained in poly(glycolide-co-ε-caprolactone) (PGCL)/silk fibroin (SF) matrix, and the formed PGCL/SF-TUBA nanofibers exhibited an uniform and smooth morphology and appropriate surface wettability. Importantly, the TUBA loaded nanofibers showed a sustained-release profile, and still maintains activity and promoted the extension of axonal. In addition, the total transection large span model of rat back and immunofluorescent labeling, histological, and neurobehavioral analysis were performed for inducing spinal cord injury at T9-10, evaluating therapeutic efficiency of SC-TUBA(+), and elucidating the mechanism of TUBA release system in vivo. All the results demonstrated the significantly reduced glial scar formation, increased nerve fiber number, inhibited inflammation, reduced demyelination and protected bladder tissue of TUBA-loaded nanofibers for spinal cord injury compared to SC-TUBA, SC and Control groups, indicating their great potential for injured spinal cord healing clinically.

Modification of cardiac disease by transgenically altered histone deacetylase 6

Histone deacetylase 6 (HDAC6) is known to deacetylate amino acid lysine in alpha-tubulin. However, the functional role of HDAC6 in the progression of cardiac disease remains uncertain. The functional role of HDAC6 in the hearts was examined using transgenic (TG) mice expressing either human wild-type HDAC6, deacetylase inactive HDAC6 (HDAC6H216A, H611A), and human HDAC6 replaced all serine or threonine residues with aspartic acid at N-terminal 1- 43 amino acids (HDAC6NT-allD) specifically in the hearts. Overexpression of wild-type HDAC6 significantly reduced acetylated tubulin levels, and overexpression of HDAC6H216A, H611A significantly increased it in the mouse hearts. Detectable acetylated tubulin disappeared in HDAC6NT-allD TG mouse hearts. Neither histological alteration nor alteration of cardiac function was observed in the HDAC6 TG mouse hearts. To analyze the role of HDAC6 and acetylated tubulin in disease conditions, we examined HDAC6 in isoprenaline-induced hypertrophy or pressure-overload hypertrophy (TAC). No obvious alteration in the heart weight/body weight ratio or gene expressions of hypertrophic markers between NTG and HDAC6NT-allD mice was observed following treatment with isoprenaline. In contrast, a marked reduction in the shortening fraction and dilated chamber dilatation was detected in the HDAC6NT-allD TG mouse hearts 2 weeks after TAC. A sustained low level of acetylated tubulin and acetylated cortactin was observed in the TAC HDAC6NT-allD TG mouse hearts. Cardiac HDAC6 activity that can regulate acetylated levels of tubulin and cortactin may be critical factors involved in cardiac disease such as pressure-overload hypertrophy.

Electroacupuncture improves TBI dysfunction by targeting HDAC overexpression and BDNF-associated Akt/GSK-3β signaling.

BackgroundAcupuncture or electroacupuncture (EA) appears to be a potential treatment in acute clinical traumatic brain injury (TBI); however, it remains uncertain whether acupuncture affects post-TBI histone deacetylase (HDAC) expression or impacts other biochemical/neurobiological events.Materials and methodsWe used behavioral testing, Western blot, and immunohistochemistry analysis to evaluate the cellular and molecular effects of EA at LI4 and LI11 in both weight drop-impact acceleration (WD)- and controlled cortical impact (CCI)-induced TBI models.ResultsBoth WD- and CCI-induced TBI caused behavioral dysfunction, increased cortical levels of HDAC1 and HDAC3 isoforms, activated microglia and astrocytes, and decreased cortical levels of BDNF as well as its downstream mediators phosphorylated-Akt and phosphorylated-GSK-3β. Application of EA reversed motor, sensorimotor, and learning/memory deficits. EA also restored overexpression of HDAC1 and HDAC3, and recovered downregulation of BDNF-associated signaling in the cortex of TBI mice.ConclusionThe results strongly suggest that acupuncture has multiple benefits against TBI-associated adverse behavioral and biochemical effects and that the underlying mechanisms are likely mediated by targeting HDAC overexpression and aberrant BDNF-associated Akt/GSK-3 signaling.

Discovery of pomalidomide-based PROTACs for selective degradation of histone deacetylase 8

Overexpression of histone deacetylase 8 (HDAC8) is associated with various diseases such as cancer. Thus, compounds that can modulate HDAC8 levels have therapeutic potential for these diseases. Based on the proteolysis targeting chimera (PROTAC) strategy, we designed and synthesized a series of HDAC8 degraders by tethering an HDAC6/8 dual inhibitor with pomalidomide (a cereblon ligand). Among them, compound ZQ-23 exhibited significant and selective degradation of HDAC8 with DC50 of 147 nM and Dmax of 93%, and exhibited no effects on HDAC1 and HDAC3. Interestingly, we found that the degradation of target protein started at ∼2 h after treatment with ZQ-23 and the maximal degradation effect was achieved at 10 h. The HDAC8 level was partially recovered within 24 h. In addition, ZQ-23 had no degrading effects on HDAC1 and HDAC3 at all concentrations, but could dose-dependently increase the levels of acetylated SMC-3 (HDAC8 substrate). Mechanism study demonstrated that ZQ-23 degraded HDAC8 through the ubiquitin-protease pathway, rather than lysosome system. Collectively, these results suggest that ZQ-23 represents a novel PROTAC-based HDAC8 degrader worthy of further investigation.

Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression

Overexpression of histone deacetylases (HDACs) in cancer commonly causes resistance to genotoxic-based therapies. Here, we report on the novel mechanism whereby overexpressed class I HDACs increase the resistance of glioblastoma cells to the SN1 methylating agent temozolomide (TMZ). The chemotherapeutic TMZ triggers the activation of the DNA damage response (DDR) in resistant glioma cells, leading to DNA lesion bypass and cellular survival. Mass spectrometry analysis revealed that the catalytic activity of class I HDACs stimulates the expression of the E3 ubiquitin ligase RAD18. Furthermore, the data showed that RAD18 is part of the O6-methylguanine-induced DDR as TMZ induces the formation of RAD18 foci at sites of DNA damage. Downregulation of RAD18 by HDAC inhibition prevented glioma cells from activating the DDR upon TMZ exposure. Lastly, RAD18 or O6-methylguanine-DNA methyltransferase (MGMT) overexpression abolished the sensitization effect of HDAC inhibition on TMZ-exposed glioma cells. Our study describes a mechanism whereby class I HDAC overexpression in glioma cells causes resistance to TMZ treatment. HDACs accomplish this by promoting the bypass of O6-methylguanine DNA lesions via enhancing RAD18 expression. It also provides a treatment option with HDAC inhibition to undermine this mechanism.

Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA. Therefore, we designed a series of harmine-based inhibitors targeting HDAC and DNA with multi-target strategy, the most potential compound 27 could bind to DNA and cause DNA damage. Furthermore 27 caused cells apoptosis through p53 signaling pathway, and exhibited significant anti-proliferation effects against HCT-116 cells (IC50 = 1.41 μM). As a DNA damage agent, 27 displayed low toxicity in normal cells. Compound 27 was demonstrated as a dual inhibitor targeting HDAC (HDAC1 IC50 = 0.022 μM and HDAC6 IC50 = 0.45 μM) and DNA, and had the potential in the treatment of solid tumor.

In silico profiling of histone deacetylase inhibitory activity of compounds isolated from Cajanus cajan

BackgroundCancer is responsible for high morbidity and mortality globally. Because the overexpression of histone deacetylases (HDACs) is one of the molecular mechanisms associated with the development and progression of some diseases such as cancer, studies are now considering inhibition of HDAC as a strategy for the treatment of cancer. In this study, a receptor-based in silico screening was exploited to identify potential HDAC inhibitors among the compounds isolated from Cajanus cajan, since reports have earlier confirmed the antiproliferative properties of compounds isolated from this plant.ResultsCajanus cajan-derived phytochemicals were docked with selected HDACs, with givinostat as the reference HDAC inhibitor, using AutodockVina and Discovery Studio Visualizer, BIOVIA, 2020. Furthermore, absorption, distribution, metabolism and excretion (ADME) drug-likeness analysis was done using the Swiss online ADME web tool. From the results obtained, 4 compounds; betulinic acid, genistin, orientin and vitexin, were identified as potential inhibitors of the selected HDACs, while only 3 compounds (betulinic acid, genistin and vitexin) passed the filter of drug-likeness. The molecular dynamic result revealed the best level of flexibility on HDAC1 and HDAC3 compared to the wild-type HDACs and moderate flexibility of HDAC7 and HDAC8.ConclusionsThe results of molecular docking, pharmacokinetics and molecular dynamics revealed that betulinic acid might be a suitable HDAC inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs. This knowledge can be used to guide experimental investigation on Cajanus cajan-derived compounds as potential HDAC inhibitors.

Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells’ Pluripotency in Bladder Cancer

Simple SummaryBladder cancer (BC) is the second most frequent cancer of the genitourinary system. More than 500,000 patients per year are diagnosed with BC, a disease which additionally results in more than 200,000 annual deaths. One of the major problems in BC treatment is that many patients cannot receive appropriate treatment due to comorbidities and the severe inflammatory side effects of therapy. The aim of our study was to assess the effect of butyrate derivatives, demonstrating that they could be beneficial for treating the tumor and also to modify the tumor microenvironment. Upon treatment with butyrate derivatives, we particularly saw increased PD-L1 surface expression and reduced pluripotency molecular markers in a hybrid BC–macrophage cell population. This is a cell population known to display an increased capacity to migrate and evade immunity. Treatment with butyrate derivatives may also provide a better chance of immunotherapy success for BC patients.Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette–Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1β. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid–tumoral hybrid population (CD11b+EPCAM+) was detected after 48 h, which indicates BC cell–macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers (SOX2, NANOG, miR-302) as compared with non-fused (CD11b−EPCAM+) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10. Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.

Artificial exosomes mediated spatiotemporal-resolved and targeted delivery of epigenetic inhibitors

BackgroundMalignant tumor is usually associated with epigenetic dysregulation, such as overexpression of histone deacetylase (HDAC), thus HDAC has emerged as a therapeutic target for cancer. Histone deacetylase inhibitor has been approved for clinical use to treat hematological cancers. However, the low solubility, short circulation lifetime, and high cytotoxicity partially limited their applications in solid tumor.MethodsThe upconversion nanoparticles (UC) modified with mesoporous silica (SUC) was used to load an HDACI, suberoylanilide hydroxamic acid (SAHA), and further camouflaged with M1 macrophage-derived exosome membranes (EMS). EMS was characterized in size and compositions. We also analyzed the epigenetic regulation induced by EMS. Furthermore, we evaluate the biodistribution and in vivo tumor inhibition after the systemic administration of EMS.ResultsThis novel style spatiotemporal-resolved drug delivery system, EMS showed a high loading efficiency of SAHA. EMS could be taken up by lung cancer cells and lead to efficient epigenetic inhibition. We found that the integrin α4β1 on M1-EM, was crucial for the homing of EMS to tumor tissues for the first time. In tumor-bearing mice, EMS showed spatiotemporal-resolved properties and facilitated the drug accumulation in the tumors, which induced superior anti-tumor effects.ConclusionThis novel style of spatiotemporal-resolved nanoparticles can be used as a theranostic platform for lung cancer therapy.Graphical