Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Isc...Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Ischemic retinopathy can be acute,such as in central or branch retinal artery occlusion,or chronic,such as with DR(Figure 1).Although the causes of retinopathies are diverse,one pathogenic event shared by these conditions is the myeloid cell response to retinal ischemia(Shahror et al.,2024a).展开更多
Diabetic foot ulcer is the most prevalent and serious lower-limb complication among individuals with diabetes,and it significantly contributes to the incidence of non-traumatic amputations.The repeated failure of diab...Diabetic foot ulcer is the most prevalent and serious lower-limb complication among individuals with diabetes,and it significantly contributes to the incidence of non-traumatic amputations.The repeated failure of diabetic wounds to heal can result in diabetic foot ulcers,inflicting considerable physical suffering and imposing substantial economic burdens on both patients and global healthcare systems because of the complexity and high costs of treatment.The mechanisms underlying the impaired healing of diabetic wounds are intricate and incompletely understood.Histone deacetylases(HDACs)are critical epigenetic regulators that catalyze the removal of acetyl or acyl groups from lysine residues in proteins,thereby modulating various biological processes,including transcription,apoptosis,and metabolism.Nevertheless,the precise roles of HDACs in diabetic wound healing remain largely unexplored.Thus,the current review describes the pivotal roles of HDACs in diabetic wound healing,focusing on their regulation of inflammatory responses,vascular dysfunction,and epithelial renewal,which are critical events in wound healing.Furthermore,we discuss the therapeutic potential of HDAC inhibitors and propose future directions for clinical application.展开更多
Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal funct...Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.展开更多
Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.Howe...Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.展开更多
Histone deacetylase 10(HDAC10)is emerging as a critical modulator of tumor immunity,chemoresistance,and transcriptional plasticity in colorectal cancer.Its suppression has been linked to altered CD8+T cell activity,in...Histone deacetylase 10(HDAC10)is emerging as a critical modulator of tumor immunity,chemoresistance,and transcriptional plasticity in colorectal cancer.Its suppression has been linked to altered CD8+T cell activity,increased p53 expres-sion,and reduced programmed death ligand 1 levels,suggesting a potential role in immune evasion.However,mechanistic understanding of HDAC10’s selective function,especially in shaping the tumor microenvironment,remains limited.We advocate for targeted investigations using isoform-selective inhibitors,functional in vivo studies,and immune subset profiling to clarify HDAC10’s therapeutic re-levance in colorectal cancer.展开更多
The Rpd3 histone deacetylase complex is a multiple-subunit complex that mediates the regulation of chromatin accessibility and gene expression.Sin3,the largest subunit of Rpd3 complex,is conserved in a broad range of ...The Rpd3 histone deacetylase complex is a multiple-subunit complex that mediates the regulation of chromatin accessibility and gene expression.Sin3,the largest subunit of Rpd3 complex,is conserved in a broad range of eukaryotes.Despite being a molecular scaffold for complex assembly,the functional sites and mechanism of action of Sin3 remain unexplored.In this study,we functionally characterized a glutamate residue(E810)in Fg Sin3,the ortholog of yeast Sin3 in Fusarium graminearum(known as wheat scab fungus).Our findings indicate that E810 was important for the functions of Fg Sin3 in regulating vegetative growth,sexual reproduction,wheat infection,and DON biosynthesis.Furthermore,the E810K missense mutation restored the reduced H4 acetylation caused by the deletion of FNG1,the ortholog of the human inhibitor of growth(ING1)gene in F.graminearum.Correspondingly,the defects of the fng1 mutant were also partially rescued by the E810K mutation in Fg Sin3.Sequence alignment and evolutionary analysis revealed that E810 residue is well-conserved in fungi,animals,and plants.Based on Alphafold2 structure modeling,E810 localized on the Fg Rpd3–Fg Sin3 interface for the formation of a hydrogen bond with Fg Rpd3.Mutation of E810 disrupts the hydrogen bond and likely affects the Fg Rpd3–Fg Sin3 interaction.Taken together,E810 of Fg Sin3 is functionally associated with Fng1 in the regulation of H4 acetylation and related biological processes,probably by affecting the assembly of the Rpd3 complex.展开更多
BACKGROUND The histone deacetylases 10(HDAC10)is a HDAC family member,yet its importance in the context of colorectal cancer(CRC)development remains incompletely understood.The present study was thus developed to expl...BACKGROUND The histone deacetylases 10(HDAC10)is a HDAC family member,yet its importance in the context of colorectal cancer(CRC)development remains incompletely understood.The present study was thus developed to explore the mechanistic importance of HDAC10 as a regulator of CRC.AIM To investigate the impact of HDAC10 on tumor growth and its regulation in tumor microenvironment(TME)in CRC,we conducted this study.METHODS The study evaluated HDAC10 expression using immunohistochemistry analyses and assessed its prognostic value in CRC patients.HDAC10 depletion CRC cell lines were generated,and its biological functions were assessed through cell counting kit-8,wound healing,and colony formation assays.Furthermore,gene set variation analysis(GSVA)was employed to explore the potential molecular mechanisms of HDAC10 in CRC.The impact of HDAC10 on TME was subsequently assessed.Finally,the study investigated the influence of HDAC10 on the response to immunotherapy and chemotherapeutic drugs in CRC.RESULTS HDAC10 expression was significantly elevated in CRC and correlated with poor prognosis in patients.Knockdown of HDAC10 reduced colon cancer cell proliferation and migration capabilities.GSVA revealed a strong association between high HDAC10 expression and immune suppression.Additionally,high HDAC10 levels were correlated with a non-inflamed TME.Finally,patients with high HDAC10 expression showed reduced sensitivity to immuno-therapy.CONCLUSION This study revealed the significance of HDAC10 in TME,therapy efficacy,and clinical prognosis in CRC,offering novel insights for therapeutic advancements in CRC.展开更多
Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have o...Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have only slightly improved patient outcomes.More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm.Among new agents,histone deacetylase inhibitors (HDACIs) are now being tested.HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression,apoptosis,cell cycle progression and angiogenesis.HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines.In the present review,the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro,as well as their antiproliferative effects in animal models are presented.HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor ef-fects,at well-tolerated doses.展开更多
Pancreatic cancer,although not very frequent,has an exceptionally high mortality rate,making it one of the most common causes of cancer mortality in developed countries.Pancreatic cancer is difficult to diagnose,allow...Pancreatic cancer,although not very frequent,has an exceptionally high mortality rate,making it one of the most common causes of cancer mortality in developed countries.Pancreatic cancer is difficult to diagnose,allowing few patients to have the necessary treatment at a relatively early stage.Despite a marginal benefit in survival,the overall response of pancreatic cancer to current systemic therapy continues to be poor,and new therapies are desperately needed.Histone deacetylase(HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors(HDACIs) have been shown to induce differentiation and cell cycle arrest,activate the extrinsic or intrinsic pathways of apoptosis,and inhibit invasion,migration and angiogenesis in different cancer cell lines.As a result of promising preclinical data,various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies.Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma.The use of HDACIs in clinical trials,in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed.Unfortunately,clinical data for HDACIs in patients with pancreatic cancer are inadequate,because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase Ⅱ/Ⅲ trials,among others with advanced solid tumors,is very limited.More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.展开更多
Parkinson＇s disease （PD） is the second most common neurodegenerative disorder and is characterized by its progressive course. The current therapies are aimed at alleviating symptoms by rescuing the unbalanced physi...Parkinson＇s disease （PD） is the second most common neurodegenerative disorder and is characterized by its progressive course. The current therapies are aimed at alleviating symptoms by rescuing the unbalanced physiological dopamine metabolism and recovery of damaged neuronal circuits. However, these strategies result in insufficient clinical benefits for many patients and fail to halt disease progression. Therefore, new therapeutic targets could serve as the gateway against PD degeneration. One pathological hallmark of PD is the formation of intracytoplasmic protein inclusions or Lewy bodies, in neurons. Recent studies have suggested that Lewy bodies are formed similarly to aggresomes, and results have supported the concept that the novel cellular organelle, the aggresome, is a cytoprotective response that sequesters and facilitates clearance of potentially toxic protein aggregates. In addition, a-tubulin deacetylase has been shown to regulate aggresome formation and rescue neural cell viability in response to misfolded protein. Therefore, the regulation of aggresome formation to trigger cellular self-protection system could arrest PD progression. The present study discusses research progress related to Lewy bodies, aggresomes, and histone deacetylases, with an emphasis on histone deacetylase 6 and sirtuin type 2.展开更多
AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) ...AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib. METHODS: Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry.RESULTS: MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21Waf/CIP1. Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multi-kinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects.CONCLUSION: The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents.展开更多
Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribut...Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribute to the pathogenesis of this disease. Our previous studies showed that an autophagic flux defect is involved in motor neuron degeneration in the SOD1G93A mouse model of ALS. Histone deacetylase 6 （HDAC6） is a class II deacetylase that promotes autophagy by inducing the fusion of autophagosomes to lysosomes. In the present study, we showed that HDAC6 expression was decreased at the onset of disease and became extremely low at the late stage in ALS mice. Using lentivirus-HDAC6 gene injection, we found that HDAC6 overexpression prolonged the lifespan and delayed the motor neuron degeneration in ALS mice. Moreover, HDAC6 induced the formation of autolysosomes and accelerated the degradation of SOD1 protein aggregates in the motor neurons of ALS mice. Collectively, our results indicate that HDAC6 has neuroprotective effects in an animal model of ALS by improving the autophagic flux in motor neurons, and autophagosome-lysosome fusion might be a therapeutic target for ALS.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)has become a great threat for people’s health.Many long noncoding RNAs are involved in the pathogenesis of HCC.SNHG15,as a tissue specific long noncoding RNAs,has been studied ...BACKGROUND Hepatocellular carcinoma(HCC)has become a great threat for people’s health.Many long noncoding RNAs are involved in the pathogenesis of HCC.SNHG15,as a tissue specific long noncoding RNAs,has been studied in many human cancers,except HCC.AIM To explore the regulatory mechanism of SNHG15 in HCC.METHODS In the present research,101 HCC patient samples,two HCC cell lines and one normal liver cell line were used.RT-qPCR and Western blot analysis were applied to detect SNHG15,miR-490-3p and histone deacetylase 2(HDAC2)expression.The regulatory mechanism of SNHG15 was investigated using CCK-8,Transwell and luciferase reporter assays.RESULTS Our research showed that up-regulation of SNHG15 was found in HCC and was related to aggressive behaviors in HCC patients.Moreover,knockdown of SNHG15 restrained HCC cell proliferation,migration and invasion.In addition,SNHG15 served as a molecular sponge for miR-490-3p.Further,miR-490-3p directly targets HDAC2.HDAC2 was involved in HCC progression by interacting with the SNHG15/miR-490-3p axis.CONCLUSION In conclusion,long noncoding RNA SNHG15 promotes HCC progression by mediating the miR-490-3p/HDAC2 axis in HCC.展开更多
Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediate...Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes （class I, II, and IV） on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs （also known as the sirtuins） are composed of a family of NAD＋-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD.展开更多
Arabidopsis thaliana histone deacetylase 1 （AtHD1 or AtHDA19）, a homolog ot yeast RPD3, is a global regulator ot many physiological and developmental processes in plants. In spite of the genetic evidence for a role ...Arabidopsis thaliana histone deacetylase 1 （AtHD1 or AtHDA19）, a homolog ot yeast RPD3, is a global regulator ot many physiological and developmental processes in plants. In spite of the genetic evidence for a role of AtHD1 in plant gene regulation and development, the biochemical and cellular properties ofAtHD 1 are poorly understood. Here we report cellular localization patterns ofAtHD 1 in vivo and histone deacetylase activity in vitro. The transient and stable expression of a green fluorescent protein （GFP）-tagged AtHD1 in onion cells and in roots, seeds and leaves of the transgenic Arabidopsis, respectively, revealed that AtHD1 is localized in the nucleus presumably in the euchromatic regions and excluded from the nucleolus. The localization patterns ofAtHD 1 are different from those of AtHD2 and AtHDA6 that are involved in nucleolus formation and silencing of transgenes and repeated DNA elements, respectively. In addition, a histone deacetylase activity assay showed that the recombinant AtHD 1 produced in bacteria demonstrated a specific histone deacetylase activity in vitro. The data suggest that AtHD 1 is a nuclear protein and possesses histone deacetylase activities responsible for global transcriptional regulation important to plant growth and development.展开更多
Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused ...Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes,by interfering with the acetylation status of nuclear histone proteins,hence the name histone deacetylase inhibitors was coined.Yet,this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation,survival and cell death induction.展开更多
TMP269 is a selective class ⅡA histone deacetylase inhibitor that has a protective effect on the central nervous system, whose specific mechanism of action is unclear. We aimed to reveal the optimal concentration of ...TMP269 is a selective class ⅡA histone deacetylase inhibitor that has a protective effect on the central nervous system, whose specific mechanism of action is unclear. We aimed to reveal the optimal concentration of TMP269 for protecting against cerebral ischemia/reperfusion injury and its neuroprotective mechanism. Male Sprague-Dawley rats were randomly divided into sham, ischemia/reperfusion, and 1, 4, 10 and 16 mg/kg TMP269 groups. Cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. TMP269 was intraperitoneally administered at different doses 0.5 hours before ischemia induction. Western blot assay and immunohistochemistry were used to detect effects of TMP269 on histone 2 acetylation. The results showed that the level of histone 2 acetylation was increased 24 hours after TMP269 injection. 2,3,5-Triphenyltetrazolium chloride staining was utilized to examine effect of TMP269 on infarct volume. The results found that different doses of TMP269 could reduce the infarct volume. Western blot assay, immunohistochemistry and Evans blue staining were employed to measure the effect of TMP269 on blood-brain barrier. The results showed that TMP269 counteracted the abnormal endothelial cell permeability changes caused by cerebral ischemia/reperfusion. Western blot assay and immunohistochemistry were used to determine the effect of TMP269 on tissue kallikrein. The results found that TMP269 up-regulated the expression of tissue kallikrein. Western blot assay further determined the optimal concentration to be 4 mg/kg. In conclusion, TMP269 plays a neuroprotective role by up-regulating the level of histone 2 acetylation, alleviating endothelial cell injury after cerebral ischemia/reperfusion, and up-regulating the expression of tissue kallikrein. The experimental protocol was approved in 2014 by the Department of Laboratory Animal Science, Fudan University, China(approval No. 20140143 C001).展开更多
AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was stud...AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS： In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 （3 d） 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis （PARP cleavage）, and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% （bile duct cancer） and 87% （gallbladder cancer） in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation （MIB-1）. CONCLUSION： Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.展开更多
The Arabidopsis thaliana RPD3-type histone deacetylases have been known to form conserved SIN3-type histone deacetylase complexes,but whether they form other types of complexes is unknown.Here,we perform affinity puri...The Arabidopsis thaliana RPD3-type histone deacetylases have been known to form conserved SIN3-type histone deacetylase complexes,but whether they form other types of complexes is unknown.Here,we perform affinity purification followed by mass spectrometry and demonstrate that the Arabidopsis RPD3-type histone deacetylases HDA6 and HDA19 interact with several previously uncharacterized proteins,thereby forming three types of plant-specific histone deacetylase complexes,which we named SANT,ESANT,and ARID.RNA-seq indicates that the newly identified components function together with HDA6 and HDA19 and coregulate the expression of a number of genes.HDA6 and HDA19 were previously thought to repress gene transcription by histone deacetylation.We find that the histone deacetylase complexes can repress gene expression via both histone deacetylation-dependent and-independent mechanisms.In the mutants of histone deacetylase complexes,the expression of a number of stressinduced genes is up-regulated,and several mutants of the histone deacetylase complexes show severe retardation in growth.Considering that growth retardation is thought to be a trade-off for an increase in stress tolerance,we infer that the histone deacetylase complexes identified in this study prevent overexpression of stress-induced genes and thereby ensure normal growth of plants under nonstress conditions.展开更多
Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie＇s disease （PD） is a localized fibrotic process of the tunica alb...Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie＇s disease （PD） is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA （siRNA）-mediated silencing of histone deacetylase 2 （HDAC2） in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-p1 （TGF-β1）. Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle α-actin and extracellular matrix proteins, including plasminogen activator inhibitor-β 1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-β1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-β1-induced extracellular matrix production by blocking TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD.展开更多
基金supported by the National Institute of Health/National Eye Institute(NIH/NEI)grants(R00 EY029373,R01 EY035658)to AYFKnights Templar Eye Foundation Research Grant to ESIntramural UAMS Hornick and Sturgis grants to AYF and ES respectively。
文摘Ischemic retinopathy is a leading cause of blindness:Ischemic retinopathies including diabetic retinopathy(DR),retinopathy of prematurity,and retinal artery and vein occlusion are major causes of visual impairment.Ischemic retinopathy can be acute,such as in central or branch retinal artery occlusion,or chronic,such as with DR(Figure 1).Although the causes of retinopathies are diverse,one pathogenic event shared by these conditions is the myeloid cell response to retinal ischemia(Shahror et al.,2024a).
基金Supported by the Guizhou Provincial Basic Research Program(Natural Science),No.ZK[2024]297.
文摘Diabetic foot ulcer is the most prevalent and serious lower-limb complication among individuals with diabetes,and it significantly contributes to the incidence of non-traumatic amputations.The repeated failure of diabetic wounds to heal can result in diabetic foot ulcers,inflicting considerable physical suffering and imposing substantial economic burdens on both patients and global healthcare systems because of the complexity and high costs of treatment.The mechanisms underlying the impaired healing of diabetic wounds are intricate and incompletely understood.Histone deacetylases(HDACs)are critical epigenetic regulators that catalyze the removal of acetyl or acyl groups from lysine residues in proteins,thereby modulating various biological processes,including transcription,apoptosis,and metabolism.Nevertheless,the precise roles of HDACs in diabetic wound healing remain largely unexplored.Thus,the current review describes the pivotal roles of HDACs in diabetic wound healing,focusing on their regulation of inflammatory responses,vascular dysfunction,and epithelial renewal,which are critical events in wound healing.Furthermore,we discuss the therapeutic potential of HDAC inhibitors and propose future directions for clinical application.
基金supported by the National Natural Science Foundation of China,No.82201582(to QT)Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT)+3 种基金General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL)CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH)Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL)the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。
文摘Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.
基金Supported by National Natural Science Foundation of China,No.32270768,No.82273970,No.32070726 and No.82370715Hubei Natural Science Foundation of China,No.2024AFB218+1 种基金National Key R&D Program of China,No.2023YFC2507904Doctoral Startup Foundation of Hubei University of Technology,No.XJ2022003901.
文摘Histone deacetylase inhibitors(HDACis),such as trichostatin A(TSA),have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes.However,emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis.Chen et al elucidate this paradox,demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis,thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma(ESCC).Furthermore,they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC.Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments.Here,we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.
文摘Histone deacetylase 10(HDAC10)is emerging as a critical modulator of tumor immunity,chemoresistance,and transcriptional plasticity in colorectal cancer.Its suppression has been linked to altered CD8+T cell activity,increased p53 expres-sion,and reduced programmed death ligand 1 levels,suggesting a potential role in immune evasion.However,mechanistic understanding of HDAC10’s selective function,especially in shaping the tumor microenvironment,remains limited.We advocate for targeted investigations using isoform-selective inhibitors,functional in vivo studies,and immune subset profiling to clarify HDAC10’s therapeutic re-levance in colorectal cancer.
基金supported by the grants from the National Natural Science Foundation of China(32102181)the Shaanxi Science Fund for Distinguished Young Scholars,China(2022JC-14)。
文摘The Rpd3 histone deacetylase complex is a multiple-subunit complex that mediates the regulation of chromatin accessibility and gene expression.Sin3,the largest subunit of Rpd3 complex,is conserved in a broad range of eukaryotes.Despite being a molecular scaffold for complex assembly,the functional sites and mechanism of action of Sin3 remain unexplored.In this study,we functionally characterized a glutamate residue(E810)in Fg Sin3,the ortholog of yeast Sin3 in Fusarium graminearum(known as wheat scab fungus).Our findings indicate that E810 was important for the functions of Fg Sin3 in regulating vegetative growth,sexual reproduction,wheat infection,and DON biosynthesis.Furthermore,the E810K missense mutation restored the reduced H4 acetylation caused by the deletion of FNG1,the ortholog of the human inhibitor of growth(ING1)gene in F.graminearum.Correspondingly,the defects of the fng1 mutant were also partially rescued by the E810K mutation in Fg Sin3.Sequence alignment and evolutionary analysis revealed that E810 residue is well-conserved in fungi,animals,and plants.Based on Alphafold2 structure modeling,E810 localized on the Fg Rpd3–Fg Sin3 interface for the formation of a hydrogen bond with Fg Rpd3.Mutation of E810 disrupts the hydrogen bond and likely affects the Fg Rpd3–Fg Sin3 interaction.Taken together,E810 of Fg Sin3 is functionally associated with Fng1 in the regulation of H4 acetylation and related biological processes,probably by affecting the assembly of the Rpd3 complex.
基金Supported by National Natural Science Foundation of China,No.82403279 and No.82303181.
文摘BACKGROUND The histone deacetylases 10(HDAC10)is a HDAC family member,yet its importance in the context of colorectal cancer(CRC)development remains incompletely understood.The present study was thus developed to explore the mechanistic importance of HDAC10 as a regulator of CRC.AIM To investigate the impact of HDAC10 on tumor growth and its regulation in tumor microenvironment(TME)in CRC,we conducted this study.METHODS The study evaluated HDAC10 expression using immunohistochemistry analyses and assessed its prognostic value in CRC patients.HDAC10 depletion CRC cell lines were generated,and its biological functions were assessed through cell counting kit-8,wound healing,and colony formation assays.Furthermore,gene set variation analysis(GSVA)was employed to explore the potential molecular mechanisms of HDAC10 in CRC.The impact of HDAC10 on TME was subsequently assessed.Finally,the study investigated the influence of HDAC10 on the response to immunotherapy and chemotherapeutic drugs in CRC.RESULTS HDAC10 expression was significantly elevated in CRC and correlated with poor prognosis in patients.Knockdown of HDAC10 reduced colon cancer cell proliferation and migration capabilities.GSVA revealed a strong association between high HDAC10 expression and immune suppression.Additionally,high HDAC10 levels were correlated with a non-inflamed TME.Finally,patients with high HDAC10 expression showed reduced sensitivity to immuno-therapy.CONCLUSION This study revealed the significance of HDAC10 in TME,therapy efficacy,and clinical prognosis in CRC,offering novel insights for therapeutic advancements in CRC.
文摘Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have only slightly improved patient outcomes.More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm.Among new agents,histone deacetylase inhibitors (HDACIs) are now being tested.HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression,apoptosis,cell cycle progression and angiogenesis.HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines.In the present review,the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro,as well as their antiproliferative effects in animal models are presented.HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor ef-fects,at well-tolerated doses.
文摘Pancreatic cancer,although not very frequent,has an exceptionally high mortality rate,making it one of the most common causes of cancer mortality in developed countries.Pancreatic cancer is difficult to diagnose,allowing few patients to have the necessary treatment at a relatively early stage.Despite a marginal benefit in survival,the overall response of pancreatic cancer to current systemic therapy continues to be poor,and new therapies are desperately needed.Histone deacetylase(HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors(HDACIs) have been shown to induce differentiation and cell cycle arrest,activate the extrinsic or intrinsic pathways of apoptosis,and inhibit invasion,migration and angiogenesis in different cancer cell lines.As a result of promising preclinical data,various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies.Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma.The use of HDACIs in clinical trials,in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed.Unfortunately,clinical data for HDACIs in patients with pancreatic cancer are inadequate,because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase Ⅱ/Ⅲ trials,among others with advanced solid tumors,is very limited.More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.
文摘Parkinson＇s disease （PD） is the second most common neurodegenerative disorder and is characterized by its progressive course. The current therapies are aimed at alleviating symptoms by rescuing the unbalanced physiological dopamine metabolism and recovery of damaged neuronal circuits. However, these strategies result in insufficient clinical benefits for many patients and fail to halt disease progression. Therefore, new therapeutic targets could serve as the gateway against PD degeneration. One pathological hallmark of PD is the formation of intracytoplasmic protein inclusions or Lewy bodies, in neurons. Recent studies have suggested that Lewy bodies are formed similarly to aggresomes, and results have supported the concept that the novel cellular organelle, the aggresome, is a cytoprotective response that sequesters and facilitates clearance of potentially toxic protein aggregates. In addition, a-tubulin deacetylase has been shown to regulate aggresome formation and rescue neural cell viability in response to misfolded protein. Therefore, the regulation of aggresome formation to trigger cellular self-protection system could arrest PD progression. The present study discusses research progress related to Lewy bodies, aggresomes, and histone deacetylases, with an emphasis on histone deacetylase 6 and sirtuin type 2.
基金a scholarship from the Sonnenfeld-Stiftung,Berlin,Germany for Viola Baradari
文摘AIM: To investigate the antiproliferative effect of the histone deacetylase (HDAC) inhibitor MS-275 on cholangiocarcinoma cells alone and in combination with conventional cytostatic drugs (gemcitabine or doxorubicin) or the novel anticancer agents sorafenib or bortezomib. METHODS: Two human bile duct adenocarcinoma cell lines (EGI-1 and TFK-1) were studied. Crystal violet staining was used for detection of cell number changes. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). Apoptosis was determined by measuring the enzyme activity of caspase-3. Cell cycle status reflected by the DNA content was detected by flow cytometry.RESULTS: MS-275 treatment potently inhibited the proliferation of EGI-1 and TFK-1 cholangiocarcinoma cells by inducing apoptosis and cell cycle arrest. MS-275-induced apoptosis was characterized by activation of caspase-3, up-regulation of Bax and down-regulation of Bcl-2. Cell cycle was predominantly arrested at the G1/S checkpoint, which was associated with induction of the cyclin-dependent kinase inhibitor p21Waf/CIP1. Furthermore, additive anti-neoplastic effects were observed when MS-275 treatment was combined with gemcitabine or doxorubicin, while combination with the multi-kinase inhibitor sorafenib or the proteasome inhibitor bortezomib resulted in overadditive anti-neoplastic effects.CONCLUSION: The growth of human cholangiocarcinoma cells can be potently inhibited by MS-275 alone or in combination with conventional cytostatic drugs or new, targeted anticancer agents.
基金supported by grants from the National Natural Science Foundation of China (81200977)the Shanghai Natural Science Foundation (14ZR1446400)+2 种基金Shanghai Rising-Star Program (15QA1403000)the PhD Innovation Fund of Shanghai Jiaotong University School of Medicine (BXJ 201218)the PhD Tutor Fund of the Ministry of Education of China (20120073110077)
文摘Amyotrophic lateral sclerosis （ALS） is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribute to the pathogenesis of this disease. Our previous studies showed that an autophagic flux defect is involved in motor neuron degeneration in the SOD1G93A mouse model of ALS. Histone deacetylase 6 （HDAC6） is a class II deacetylase that promotes autophagy by inducing the fusion of autophagosomes to lysosomes. In the present study, we showed that HDAC6 expression was decreased at the onset of disease and became extremely low at the late stage in ALS mice. Using lentivirus-HDAC6 gene injection, we found that HDAC6 overexpression prolonged the lifespan and delayed the motor neuron degeneration in ALS mice. Moreover, HDAC6 induced the formation of autolysosomes and accelerated the degradation of SOD1 protein aggregates in the motor neurons of ALS mice. Collectively, our results indicate that HDAC6 has neuroprotective effects in an animal model of ALS by improving the autophagic flux in motor neurons, and autophagosome-lysosome fusion might be a therapeutic target for ALS.
文摘BACKGROUND Hepatocellular carcinoma(HCC)has become a great threat for people’s health.Many long noncoding RNAs are involved in the pathogenesis of HCC.SNHG15,as a tissue specific long noncoding RNAs,has been studied in many human cancers,except HCC.AIM To explore the regulatory mechanism of SNHG15 in HCC.METHODS In the present research,101 HCC patient samples,two HCC cell lines and one normal liver cell line were used.RT-qPCR and Western blot analysis were applied to detect SNHG15,miR-490-3p and histone deacetylase 2(HDAC2)expression.The regulatory mechanism of SNHG15 was investigated using CCK-8,Transwell and luciferase reporter assays.RESULTS Our research showed that up-regulation of SNHG15 was found in HCC and was related to aggressive behaviors in HCC patients.Moreover,knockdown of SNHG15 restrained HCC cell proliferation,migration and invasion.In addition,SNHG15 served as a molecular sponge for miR-490-3p.Further,miR-490-3p directly targets HDAC2.HDAC2 was involved in HCC progression by interacting with the SNHG15/miR-490-3p axis.CONCLUSION In conclusion,long noncoding RNA SNHG15 promotes HCC progression by mediating the miR-490-3p/HDAC2 axis in HCC.
基金This study was supported by grants from the National 973 Basic Research Program of China，the National Nature Science Foundation of China，Foundation of Program for New Century Excellent Talents in University (NCET-11-0311) to Yi F，Program for Changjiang Scholars and Innovative Research Team in University，the Special Financial Grant from the China Postdoctoral Science Foundation，the China Postdoctoral Science Foundation，the Shandong Province Post-doctoral Innovation Foundation
文摘Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes （class I, II, and IV） on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs （also known as the sirtuins） are composed of a family of NAD＋-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD.
基金We thank Mary Bryk and Timothy Hall for critical suggestions to improve the manuscript,David Stelly and Keerti Rathore for assistance in GFP localization studies in onion cells,and Stanislav Vitha in the Microscopy and Imaging Center at Texas A&M University for technical support for epifluorescence microscopic image analysis in the transgenic plants.The work is supported by grants from the National Institutes of Health(GM067015)the National Science Foundation Plant Genome Research Program(DBI0077774)to Z J C.
文摘Arabidopsis thaliana histone deacetylase 1 （AtHD1 or AtHDA19）, a homolog ot yeast RPD3, is a global regulator ot many physiological and developmental processes in plants. In spite of the genetic evidence for a role of AtHD1 in plant gene regulation and development, the biochemical and cellular properties ofAtHD 1 are poorly understood. Here we report cellular localization patterns ofAtHD 1 in vivo and histone deacetylase activity in vitro. The transient and stable expression of a green fluorescent protein （GFP）-tagged AtHD1 in onion cells and in roots, seeds and leaves of the transgenic Arabidopsis, respectively, revealed that AtHD1 is localized in the nucleus presumably in the euchromatic regions and excluded from the nucleolus. The localization patterns ofAtHD 1 are different from those of AtHD2 and AtHDA6 that are involved in nucleolus formation and silencing of transgenes and repeated DNA elements, respectively. In addition, a histone deacetylase activity assay showed that the recombinant AtHD 1 produced in bacteria demonstrated a specific histone deacetylase activity in vitro. The data suggest that AtHD 1 is a nuclear protein and possesses histone deacetylase activities responsible for global transcriptional regulation important to plant growth and development.
基金Supported by Supported by a Research Grant of the University Medical Center Giessen and Marburg
文摘Inhibitors of protein deacetylases have recently been established as a novel therapeutic principle for several human diseases,including cancer.The original notion of the mechanism of action of these compounds focused on the epigenetic control of transcriptional processes, especially of tumor suppressor genes,by interfering with the acetylation status of nuclear histone proteins,hence the name histone deacetylase inhibitors was coined.Yet,this view could not explain the high specificity for tumor cells and recent evidence now suggests that non-histone proteins represent major targets for protein deacetylase inhibitors and that the post-translational modification of the acetylome is involved in various cellular processes of differentiation,survival and cell death induction.
基金supported by the National Natural Science Foundation of China,No.81501134(to ZW)
文摘TMP269 is a selective class ⅡA histone deacetylase inhibitor that has a protective effect on the central nervous system, whose specific mechanism of action is unclear. We aimed to reveal the optimal concentration of TMP269 for protecting against cerebral ischemia/reperfusion injury and its neuroprotective mechanism. Male Sprague-Dawley rats were randomly divided into sham, ischemia/reperfusion, and 1, 4, 10 and 16 mg/kg TMP269 groups. Cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. TMP269 was intraperitoneally administered at different doses 0.5 hours before ischemia induction. Western blot assay and immunohistochemistry were used to detect effects of TMP269 on histone 2 acetylation. The results showed that the level of histone 2 acetylation was increased 24 hours after TMP269 injection. 2,3,5-Triphenyltetrazolium chloride staining was utilized to examine effect of TMP269 on infarct volume. The results found that different doses of TMP269 could reduce the infarct volume. Western blot assay, immunohistochemistry and Evans blue staining were employed to measure the effect of TMP269 on blood-brain barrier. The results showed that TMP269 counteracted the abnormal endothelial cell permeability changes caused by cerebral ischemia/reperfusion. Western blot assay and immunohistochemistry were used to determine the effect of TMP269 on tissue kallikrein. The results found that TMP269 up-regulated the expression of tissue kallikrein. Western blot assay further determined the optimal concentration to be 4 mg/kg. In conclusion, TMP269 plays a neuroprotective role by up-regulating the level of histone 2 acetylation, alleviating endothelial cell injury after cerebral ischemia/reperfusion, and up-regulating the expression of tissue kallikrein. The experimental protocol was approved in 2014 by the Department of Laboratory Animal Science, Fudan University, China(approval No. 20140143 C001).
文摘AIM： To investigate in vitro and in vivo therapeutic effects of histone deacetylase inhibitors NVP-LAQ824 and NVP-LBH589 on biliary tract cancer. METHODS： Cell growth inhibition by NVP-LAQ824 and NVP-LBH589 was studied in vitro in 7 human biliary tract cancer cell lines by MTT assay. In addition, the antitumoral effect of NVP-LBH589 was studied in a chimeric mouse model. Anti-tumoral drug mechanism was assessed by immunoblotting for acH4 and p21^WAFl/CIP-1, PARP assay, cell cycle analysis, TUNEL assay, and immunhistochemistry for MIB-1. RESULTS： In vitro treatment with both compounds significantly suppressed the growth of all cancer cell lines [mean IC50 （3 d） 0.11 and 0.05 μmol/L, respectively], and was associated with hyperacetylation of nucleosomal histone H4, increased expression of p21^WAF-1/CIP-1, induction of apoptosis （PARP cleavage）, and cell cycle arrest at G2/M checkpoint. After 28 d, NVP- LBH589 significantly reduced tumor mass by 66% （bile duct cancer） and 87% （gallbladder cancer） in vivo in comparison to placebo, and potentiated the efficacy of gemcitabine. Further analysis of the tumor specimens revealed increased apoptosis by TUNEL assay and reduced cell proliferation （MIB-1）. CONCLUSION： Our findings suggest that NVP-LBH589 and NVP-LAQ824 are active against human biliary tract cancer in vitro. In addition, NVP-LBH589 demonstrated significant in vivo activity and potentiated the efficacy of gemcitabine. Therefore, further clinical evaluation of this new drug for the treatment of biliary tract cancer is recommended.
基金supported by the National Natural Science Foundation of China(32025003)by the National Key Research and Development Program of China(2016YFA0500801)from the Chinese Ministry of Science and Technology。
文摘The Arabidopsis thaliana RPD3-type histone deacetylases have been known to form conserved SIN3-type histone deacetylase complexes,but whether they form other types of complexes is unknown.Here,we perform affinity purification followed by mass spectrometry and demonstrate that the Arabidopsis RPD3-type histone deacetylases HDA6 and HDA19 interact with several previously uncharacterized proteins,thereby forming three types of plant-specific histone deacetylase complexes,which we named SANT,ESANT,and ARID.RNA-seq indicates that the newly identified components function together with HDA6 and HDA19 and coregulate the expression of a number of genes.HDA6 and HDA19 were previously thought to repress gene transcription by histone deacetylation.We find that the histone deacetylase complexes can repress gene expression via both histone deacetylation-dependent and-independent mechanisms.In the mutants of histone deacetylase complexes,the expression of a number of stressinduced genes is up-regulated,and several mutants of the histone deacetylase complexes show severe retardation in growth.Considering that growth retardation is thought to be a trade-off for an increase in stress tolerance,we infer that the histone deacetylase complexes identified in this study prevent overexpression of stress-induced genes and thereby ensure normal growth of plants under nonstress conditions.
文摘Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie＇s disease （PD） is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA （siRNA）-mediated silencing of histone deacetylase 2 （HDAC2） in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDAC2 siRNA and then stimulated with transforming growth factor-p1 （TGF-β1）. Protein was extracted from treated fibroblasts for Western blotting and the membranes were probed with antibody to phospho-Smad2/Smad2, phospho-Smad3/Smad3, smooth muscle α-actin and extracellular matrix proteins, including plasminogen activator inhibitor-β 1, fibronectin, collagen I and collagen IV. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-β1-induced nuclear translocation of Smad2/3 in fibroblasts. Knockdown of HDAC2 in PD fibroblasts abrogated TGF-β1-induced extracellular matrix production by blocking TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts. Decoding the individual function of the HDAC isoforms by use of siRNA technology, preferably siRNA for HDAC2, may lead to the development of specific and safe epigenetic therapies for PD.
