Abstract 238: Class I HDAC inhibition prevents Ncx1 upregulation by stabilizing an HDAC5-HDAC1/Sin3a Repressor Complex during cardiac hypertrophy.

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Sabina Wang ◽  
Lillianne G Harris ◽  
Santhosh Mani ◽  
Donald Menick
Keyword(s):  
Cardiac Hypertrophy ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Class I ◽  
Proximal Promoter ◽  
Hdac Inhibition ◽  
Repressor Complex

Cardiac hypertrophy is often associated with the activation of signaling pathways that perpetuate altered calcium efflux and influx. One gene that is upregulated and contributes to altered intracellular calcium concentrations and worsening contractility during cardiac hypertrophy is the Sodium Calcium Exchanger ( Ncx1 ). Molecular studies implicate histone deacetylases (HDACs) in possibly regulating the expression of this gene. Our recent work reveals that HDAC1, HDAC5 and Sin3a interact and are recruited to the Ncx1 promoter through the Nkx2.5 transcription factor. Interestingly, we observed greater associated/interaction of the HDAC1-HDAC5/Sin3a repressor complex upon broad HDAC inhibition. Taken together, we hypothesized that HDAC inhibition, stabilizes an HDAC1-HDAC5/Sin3a repressor complex during cardiac hypertrophy. We addressed this hypothesis by treating isolated adult cardiomyocytes with class specific HDAC inhibitors since HDAC1 is a Class I HDAC and HDAC5 is a Class IIa HDAC. Co-Immunoprecipitation (Co-IP) revealed a greater association of repressor complex molecules in the presence of Entinostat, a Class I HDAC inhibitor compared to both non-treated control and TSA, a broad HDAC inhibitor (n=3). These works show enhanced recruitment Sin3a (co-repressor) at the proximal promoter of NCX1 as demonstrated by Chromatin-Immunoprecipitation (ChIP) (n=3). To test whether these observations translated into in vivo models, we subjected mice to transaortic constriction (TAC) to induce hypertrophy. In this model, Co-IP revealed results that similar to our in vitro studies with greater immuno- detection of repressor complex component, Sin3a after immune-precipitation with HDAC1. Furthermore, our ChIP data showed a greater PCR product amplification of proximal Ncx1 promoter, from experimental groups that were subjected to Entinostat (n=3). Our cumulative data suggests that Class I HDAC inhibition stabilizes a repressor complex on the Ncx1 promoter that hinders hypertrophy- mediated Ncx1 upregulation. Class specific HDAC inhibition may be useful in the stabilization and repression of aberrantly expressed genes that contribute to poor clinical outcomes in cardiac hypertrophy.

scholarly journals HDAC inhibitors impair Fshb subunit expression in murine gonadotrope cells

2019 ◽  
Vol 62 (2) ◽  
pp. 67-78 ◽  
Author(s):  
Gauthier Schang ◽  
Chirine Toufaily ◽  
Daniel J Bernard
Keyword(s):  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Class I ◽  
Subunit Expression ◽  
Beta Subunit Gene ◽  
Underlying Mechanisms

Fertility is dependent on follicle-stimulating hormone (FSH), a product of gonadotrope cells of the anterior pituitary gland. Hypothalamic gonadotropin-releasing hormone (GnRH) and intra-pituitary activins are regarded as the primary drivers of FSH synthesis and secretion. Both stimulate expression of the FSH beta subunit gene (Fshb), although the underlying mechanisms of GnRH action are poorly described relative to those of the activins. There is currently no consensus on how GnRH regulates Fshb transcription, as results vary across species and between in vivo and in vitro approaches. One of the more fully developed models suggests that the murine Fshb promoter is tonically repressed by histone deacetylases (HDACs) and that GnRH relieves this repression, at least in immortalized murine gonadotrope-like cells (LβT2 and αT3-1). In contrast, we observed that the class I/II HDAC inhibitor trichostatin A (TSA) robustly inhibited basal, activin A-, and GnRH-induced Fshb mRNA expression in LβT2 cells and in primary murine pituitary cultures. Similar results were obtained with the class I specific HDAC inhibitor, entinostat, whereas two class II-specific inhibitors, MC1568 and TMP269, had no effects on Fshb expression. Collectively, these data suggest that class I HDACs are positive, not negative, regulators of Fshb expression in vitro and that, contrary to earlier reports, GnRH may not stimulate Fshb by inhibiting HDAC-mediated repression of the gene.

scholarly journals HDAC inhibition reduces white matter injury after intracerebral hemorrhage

2020 ◽  
pp. 0271678X2094261
Author(s):  
Heng Yang ◽  
Wei Ni ◽  
Pengju Wei ◽  
Sicheng Li ◽  
Xinjie Gao ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Macrophage Polarization ◽  
Conditional Knockout ◽  
White Matter Injury ◽  
Hdac Inhibition

Inhibition of histone deacetylases (HDACs) has been shown to reduce inflammation and white matter damage after various forms of brain injury via modulation of microglia/macrophage polarization. Previously we showed that the HDAC inhibitor scriptaid could attenuate white matter injury (WMI) after ICH. To access whether modulation of microglia/macrophage polarization might underlie this protection, we investigated the modulatory role of HDAC2 in microglia/macrophage polarization in response to WMI induced by intracerebral hemorrhage (ICH) and in primary microglia and oligodendrocyte co-cultures. HDAC2 activity was inhibited via conditional knockout of the Hdac2 gene in microglia or via administration of scriptaid. Conditional knockout of the Hdac2 gene in microglia and HDAC inhibition with scriptaid both improved neurological functional recovery and reduced WMI after ICH. Additionally, HDAC inhibition shifted microglia/macrophage polarization toward the M2 phenotype and reduced proinflammatory cytokine secretion after ICH in vivo. In vitro, a transwell co-culture model of microglia and oligodendrocytes also demonstrated that the HDAC inhibitor protected oligodendrocytes by modulating microglia polarization and mitigating neuroinflammation. Moreover, we found that scriptaid decreased the expression of pJAK2 and pSTAT1 in cultured microglia when stimulated with hemoglobin. Thus, HDAC inhibition ameliorated ICH-mediated neuroinflammation and WMI by modulating microglia/macrophage polarization.

Abstract 239: Selective Class I and II Histone Deacetylation Inhibitors Alter Stability of HDAC-Corepressor Complexes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hsiao C Wang ◽  
Lillianne G Harris ◽  
James C Chou ◽  
Santhosh Mani ◽  
Donald Menick
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Hdac Inhibitors ◽  
Class I ◽  
Proximal Promoter ◽  
Repressor Complex ◽  
The Stability

Introduction: Alterations in expression and activity of different genes have been implicated in the pathogenesis of heart failure. Our lab has shown that HDAC-repressor complexes play a critical role in the upregulation Sodium Calcium Exchanger ( Ncx1) and HDAC inhibition causes changes that attenuated cardiac remodeling during cardiac hypertrophy and heart failure. Thus, treatment with HDAC inhibitors has been proposed as a potential strategy for treatment of cardiac hypertrophy and heart failure. HDAC inhibitors repress deacetylase activity but we propose that they also affect HDAC confirmation and interaction with other protein factors. We hypothesize that HDAC inhibitors affect the stability of the co-repressor complex with specific transcription factors and that this effect is dependent on the transcription factor. Results: Inhibition of HDACs in adult cardiomyocytes results in the greater stabilization of HDACs with co-repressor molecules that were recruited to the NCX1 promoter through Nkx2.5 transcription factor. HDAC class I specific inhibitor, MS 275 demonstrated stronger association between HDACs and co-repressors while other Class I inhibitors, PD106 and BML 210 failed on showing this phenomenal. The results suggested that class I HDACs inhibitors may affect formations of HDAC-complex via alternated active site interactions other than chelating with zinc binding domain. These results compliment ChIP experiments which also demonstrate the different recruitments of Sin3a at the proximal promoter of NCX1. In vivo analysis on HDAC5 knockout mice reveal that the Sin3a-HDAC1/2 repressor complex is not recruited to the Ncx1 promoter in the absence of HDAC5, indicating not only Class I HDAC but also Class II HDACs play an important role on HDAC-complex formation. Conclusions: This work gives insight into part of the molecular mechanism of how HDAC inhibitors can affect the stability of the HDAC co-repressor complex in cardiac hypertrophy and heart failure. In addition, we demonstrated the Class IIa HDACs are required for the recruitment of the Sin3a/HDAC1/2 co-repressor complex to specific transcription factors on the target promoter.

Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma

Blood ◽  
2010 ◽  
Vol 116 (3) ◽  
pp. 406-417 ◽  
Author(s):  
Jiro Kikuchi ◽  
Taeko Wada ◽  
Rumi Shimizu ◽  
Tohru Izumi ◽  
Miyuki Akutsu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Class I ◽  
Transcriptional Level ◽  
Critical Pathways ◽  
Histone Hyperacetylation

Abstract Bortezomib is now widely used for the treatment of multiple myeloma (MM); however, its action mechanisms are not fully understood. Despite the initial results, recent investigations have indicated that bortezomib does not inactivate nuclear factor-κB activity in MM cells, suggesting the presence of other critical pathways leading to cytotoxicity. In this study, we show that histone deacetylases (HDACs) are critical targets of bortezomib, which specifically down-regulated the expression of class I HDACs (HDAC1, HDAC2, and HDAC3) in MM cell lines and primary MM cells at the transcriptional level, accompanied by reciprocal histone hyperacetylation. Transcriptional repression of HDACs was mediated by caspase-8–dependent degradation of Sp1 protein, the most potent transactivator of class I HDAC genes. Short-interfering RNA-mediated knockdown of HDAC1 enhanced bortezomib-induced apoptosis and histone hyperacetylation, whereas HDAC1 overexpression inhibited them. HDAC1 overexpression conferred resistance to bortezomib in MM cells, and administration of the HDAC inhibitor romidepsin restored sensitivity to bortezomib in HDAC1-overexpressing cells both in vitro and in vivo. These results suggest that bortezomib targets HDACs via distinct mechanisms from conventional HDAC inhibitors. Our findings provide a novel molecular basis and rationale for the use of bortezomib in MM treatment.

scholarly journals Selective inhibition of HDAC2 by magnesium valproate attenuates cardiac hypertrophy

2017 ◽  
Vol 95 (3) ◽  
pp. 260-267 ◽  
Author(s):  
Suchi Raghunathan ◽  
Ramesh K. Goyal ◽  
Bhoomika M. Patel
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dna ◽  
Cardiac Hypertrophy ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Selective Inhibition ◽  
Class Ii ◽  
Class I ◽  
Hdac Inhibition ◽  
Dna Concentration

The regulatory paradigm in cardiac hypertrophy involves alterations in gene expression that is mediated by chromatin remodeling. Various data suggest that class I and class II histone deacetylases (HDACs) play opposing roles in the regulation of hypertrophic pathways. To address this, we tested the effect of magnesium valproate (MgV), an HDAC inhibitor with 5 times more potency on class I HDACs. Cardiac hypertrophy was induced by partial abdominal aortic constriction in Wistar rats, and at the end of 6 weeks, we evaluated hypertrophic, hemodynamic, and oxidative stress parameters, and mitochondrial DNA concentration. Treatment with MgV prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress, and increased mitochondrial DNA concentration. MgV treatment also increased the survival rate of the animals as depicted by the Kaplan–Meier curve. Improvement in hypertrophy due to HDAC inhibition was further confirmed by HDAC mRNA expression studies, which revealed that MgV decreases expression of pro-hypertrophic HDAC (i.e., HDAC2) without altering the expression of anti-hypertrophic HDAC5. Selective class I HDAC inhibition is required for controlling cardiac hypertrophy. Newer HDAC inhibitors that are class I inhibitors and class II promoters can be designed to obtain “pan” or “dual” natural HDAC “regulators”.

scholarly journals Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xuejie Jiang ◽  
Ling Jiang ◽  
Jiaying Cheng ◽  
Fang Chen ◽  
Jinle Ni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Hdac Inhibitors ◽  
Annexin V ◽  
Fluorescein Isothiocyanate ◽  
Gli 1 ◽  
Acute Myeloid

Abstract Background Epigenetic dysregulation plays important roles in leukemogenesis and the progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate the acetylation and deacetylation of nuclear histones. Aberrant activation of HDACs results in uncontrolled proliferation and blockade of differentiation, and HDAC inhibition has been investigated as epigenetic therapeutic strategy against AML. Methods Cell growth was assessed with CCK-8 assay, and apoptosis was evaluated by flow cytometry in AML cell lines and CD45 + and CD34 + CD38- cells from patient samples after staining with Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI). EZH2 was silenced with short hairpin RNA (shRNA) or overexpressed by lentiviral transfection. Changes in signaling pathways were detected by western blotting. The effect of chidamide or EZH2-specific shRNA (shEZH2) in combination with adriamycin was studied in vivo in leukemia-bearing nude mouse models. Results In this study, we investigated the antileukemia effects of HDAC inhibitor chidamide and its combinatorial activity with cytotoxic agent adriamycin in AML cells. We demonstrated that chidamide suppressed the levels of EZH2, H3K27me3 and DNMT3A, exerted potential antileukemia activity and increased the sensitivity to adriamycin through disruption of Smo/Gli-1 pathway and downstream signaling target p-AKT in AML cells and stem/progenitor cells. In addition to decreasing the levels of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologically by chidamide or genetically by shEZH2 suppressed the activity of Smo/Gli-1 pathway and increased the antileukemia activity of adriamycin against AML in vitro and in vivo. Conclusions Inhibition of EZH2 by chidamide has antileukemia activity and increases the chemosensitivity to adriamycin through Smo/Gli-1 pathway in AML cells (Fig. 5). These findings support the rational combination of HDAC inhibitors and chemotherapy for the treatment of AML.

scholarly journals Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939

2012 ◽  
Vol 56 (7) ◽  
pp. 3849-3856 ◽  
Author(s):  
Subathdrage D. M. Sumanadasa ◽  
Christopher D. Goodman ◽  
Andrew J. Lucke ◽  
Tina Skinner-Adams ◽  
Ishani Sahama ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Antimalarial Activity ◽  
Hdac Inhibitors ◽  
Parasite Life Cycle ◽  
Nonhistone Proteins ◽  
Content Type

ABSTRACTHistone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, thein vitroandin vivoantiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth ofPlasmodium falciparumasexual-stage parasitesin vitro(50% inhibitory concentration [IC50], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited thein vitrogrowth of exoerythrocytic-stagePlasmodiumparasites in liver cells (IC50, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimentalin vivomurine model of cerebral malaria, orally administered SB939 significantly inhibitedP. bergheiANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.

Potent Induction of Human γ Globin Gene Expression by Largazole, a New Histone Deacetylase Inhibitor.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2022-2022
Author(s):  
Hua Cao ◽  
Rui Gao Fei ◽  
Albert A. Bowers ◽  
Thomas J. Greshock ◽  
Tenaya Newkirt ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Globin Gene ◽  
Control Level ◽  
Hdac Inhibitors ◽  
Fetal Hemoglobin ◽  
Vitro Effect

Abstract Abstract 2022 Poster Board I-1044 Previous studies have demonstrated that Histone Deacetylase (HDAC) inhibitors such as butyrate and several short chain fatty acids, can induce fetal hemoglobin in humans and animal models; however induction of Hb F is achieved in relatively high concentrations of these compounds. We have previously investigated the induction of human γ globin gene activity by the prototypical HDAC inhibitor, FK228. The results demonstrated that FK228 is a more potent γ globin gene inducer compared to other HDAC inhibitors we have tested before (Am J Hematol. 12:981). In this study, we investigated the induction of human γ globin gene function of largazole and it's thiol analogue in vitro in cultures of normal human adult BFUe and in vivo in the mice carrying a human γ globin transgene. Largazole is a HDAC inhibitor which was recently isolated from a marine vyanobacterium by Luesch and co-workers. Structural features of largazole, a macrocyclic depsopeptide, closely resemble those of FK228, FR901375 and spiruchostatin. We have reported that largazole and numerous synthetic analogues are highly potent Class I histone deacetylase inhibitors (J Am Chem Soc. 130:11219, J Am Chem Soc. 2009 Feb 4). We used flow cytometry to measure the in vitro effect of largazole and it's derivatives on the frequency of HbF-positive erythroblasts in BFUe cultures from normal individuals; real-time quantitative PCR (RT-qPCR) and high performance liquid chromatography (HPLC) were used to measure the in vivo effects of largazole on human γ globin induction in γ transgenic mice carrying a human γ globin gene.. Our results show that largazole and it's thiol derivative are potent γ hemoglobin gene inducers. In the human BFUe cultures, largazole increased the levels of fetal hemoglobin positive cells from 21.9% (control level) to 62.8% at a concentration of 0.1μM; largazole thiol increased the levels of fetal hemoglobin positive cells to 62.0% at a concentration of 1μM. Transgenic mice carrying the human μLCR Aγ construct continue to express the human γ gene in the adult stage (Blood. 77:1326). Largazole was administered through IP injection at the dosages of 0.3mg/kg/day and 0.6mg/kg/day, 5 days per week, for 2 weeks to two cohorts of transgenic mice. Largazole at the dose of 0.3mg/kg/day increased the level of human γ mRNA at the end of injection by 160.7%; at a dose of 0.6mg/kg/day human γ mRNA increased by 174.7%. At the 0.6mg/kg/day dosage the level of fetal hemoglobin in the peripheral blood of the animals increased by 3.4 and 3.2 fold at day 21 and day 28, respectively. These results provide strong in vitro and in vivo evidence that Largazole and it's thiol analogue are potent HbF inducers acting at low concentrations, and thus provide promising alternatives to compounds currently considered for induction of Hb F in patients with sickle cell disease and thalassemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Sorabh Sharma ◽  
Rajeev Taliyan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Clinical Manifestations ◽  
Future Research

The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in bothin vivoandin vitromodels of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

scholarly journals Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Cinzia Lanzi ◽  
Enrica Favini ◽  
Laura Dal Bo ◽  
Monica Tortoreto ◽  
Noemi Arrighetti ◽  
...  
Keyword(s):  
Synovial Sarcoma ◽  
Cell Response ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Combined Treatment ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Xenograft Model

Abstract Background Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. Methods Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. Results SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. Conclusions The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.

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