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histone deacetylase OsHDA706 increases salt tolerance via H4K5/K8 deacetylation of OsPP2C49 in rice

Journal of Integrative Plant Biology 2023年第6期65卷 1394-1407页

作者： Kai Liu Jijin Chen Shang Sun Xu Chen Xinru Zhao Yingying Hu Guoxiao Qi Xiya Li Bo Xu Jun Miao Chao Xue Yong Zhou Zhiyun Gong Jiangsu Key Laboratory of Crop Genomics and Molecular Breeding/Key Laboratory of Plant Functional Genomics of the Ministry of Education/Jiangsu Key Laboratory of Crop Genetics and Physiology Agricultural College of Yangzhou UniversityYangzhou 225009China Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops Yangzhou UniversityYangzhou 225009China Institute of Lianyungang Agricultural Science of Xuhuai Area Lianyungang 222006China

High salt is a major environmental factor that threatens plant growth and development.Increasing evidence indicates that histone acetylation is involved in plant responses to various abiotic stress;however,the underlying epigenetic regulatory mechanisms remain poorly understood.In this study,we revealed that the histone deacetylase OsHDA706 epigenetically regulates the expression of salt stress response genes in rice(Oryza sativa L.).OsHDA706 localizes to the nucleus and cytoplasm and OsHDA706 expression is significantly induced under salt stress.Moreover,oshda706 mutants showed a higher sensitivity to salt stress than the wild-type.In vivo and in vitro enzymatic activity assays demonstrated that OsHDA706 specifically regulates the deacetylation of lysines 5 and 8 on histone H4(H4K5and H4K8).By combining chromatin immunoprecipitation and mRNA sequencing,we identified the clade A protein phosphatase 2C gene,OsPP2C49,which is involved in the salt response as a direct target of H4K5 and H4K8 acetylation.We found that the expression of OsPP2C49 is induced in the oshda706 mutant under salt stress.Furthermore,the knockout of OsPP2C49 enhances plant tolerance to salt stress,while its overexpression has the opposite effect.Taken together,our results indicate that OsHDA706,a histone H4 deacetylase,participates in the salt stress response by regulating the expression of OsPP2C49 via H4K5 and H4K8 deacetylation.

关键词： histone deacetylase OsHDA706 OsPP2C49 rice salt stress

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histone deacetylase Genes in Arabidopsis Development

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Journal of Integrative Plant Biology 2008年第7期50卷 875-885页

作者： Courtney Hollende Department of Cell Biology and Molecular Genetics University of Maryland College ParkMaryland 20742USA

histone acetylation and deacetylation are directly connected with transcriptional activation and silencing in eukaryotes. Gene families for enzymes that accomplish these histone modifications show surprising complexity in domain organization, tissue-specific expression, and function. This review is focused on the family of histone deacetylases （HDACs） that remove the acetyl group from core histone tails, resulting in a ＂closed＂ chromatin and transcriptional repression. In Arabidopsis, 18 HDAC genes are divided into three different types - RPD3-1ike, HD-tuin and sirtuin - with two or more members in each type. The structural feature of each HDAC class, the expression profile of each HDAC gene during development and functional insights of important family members are summarized here. It is clear that HDACs are an important class of global transcriptional regulators that play crucial roles in plant development, defense, and adaptation.

关键词： chromatin epigenetic regulation gene silencing histone deacetylase plant development

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Repressing iron overload ameliorates central poststroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

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Neural Regeneration Research 2024年第12期19卷 2708-2722页

作者： He Fang Mengjie Li Jingchen Yang Shunping Ma Li Zhang Hongqi Yang Qiongyan Tang Jing Cao Weimin Yang Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina Department of Molecular Neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijingChina Department of Nutrition The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan ProvinceChina Department of Neurology Henan Provincial People’s HospitalZhengzhouHenan ProvinceChina Department of Human Anatomy School of Basic Medical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina Neuroscience Research Institute Zhengzhou University Academy of Medical SciencesZhengzhouHenan ProvinceChina

Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.

关键词： central post-stroke pain hemorrhagic stroke histone deacetylase iron overload voltage-gated potassium ion channel 1.2

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Curcumin,a potent anti-tumor reagent,is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation

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Acta Pharmacologica Sinica 2005年第5期26卷 603-609页

作者： Hong-li LIU~2,Yan CHEN~(2,3),Guo-hui CUI~2,Jian-feng ZHOU~4~2Department of Hematology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China.~4Department of Hematology.Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan430030,China Department of Hematology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China Department of Hematology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Aim:To investigate curcumin(diferuloylmethane)induced apoptosis and its mo-lecular mechanism of action in B-NHL cell line Raji cells.Methods:Raji cells werecultured in RPMI-1640 medium and treated with curcumin in different concentra-tions.3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium(MTT)assay wasused to detect growth inhibition and Hoechst 33258 staining was used to detectapoptosis.Immunocytochemistry and Western blot were used to detect the ex-pressions of histone deacetylase 1,3,and 8(HDAC 1,HDAC3,and HDACS)andacetylated histone H4(Ac-histone H4)protein.Results:Curcumin inhibited theproliferation of B-NHL cell line Raji cells with a 36-h IC50value of 24.1±2.0μmol/L.Hoechst 33258 staining showed that curcumin could induce Raji cell apoptosis.The expression levels of HDAC1,HDAC3,and HDAC8 proteins were downregulat-ed following curcumin treatment in Raji cells,whereas Ac-histone H4 protein expres-sion was upregulated after treatment with curcumin.Conclusion:Curcumin,as anew member of the histone deacetylase inhibitors,can inhibit the expression ofclass I HDACs(HDAC1,HDAC3,and HDAC8),and can increase the expressionof Ac-histone H4 in Raji cells.Curcumin plays an important role in regulatingB-NHL cell line Raji cell proliferation and apoptosis.

关键词： curcumin histone deacetylase acetylated histone H4 Raji

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Evodiamine-inspired dual inhibitors of histone deacetylase 1(HDAC1) and topoisomerase 2(TOP2) with potent antitumor activity

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Acta Pharmaceutica Sinica B 2020年第7期10卷 1294-1308页

作者： Yahui Huang Shuqiang Chen Shanchao Wu Guoqiang Dong Chunquan Sheng Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1(HDAC1)and topoisomerase 2(TOP2)dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor potency.Particularly,compound 30 a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model(TGI=75.2%,150 mg/kg,p.o.)without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their combination.Taken together,this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

关键词： Evodiamine histone deacetylase Topoisomerase Dual inhibitors Antitumor activity

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Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie＇s plaque

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Asian Journal of Andrology 2013年第5期15卷 640-645页

作者： Ji-Kan Ryu Woo-Jean Kim Min-Ji Choi Jin-Mi Park Kang-Moon Song Mi-Hye Kwon Nando-Dulal Das Ki-Dong Kwon Dulguun Batbold Guo-Nan Yin Jun-Kyu Suh National Research Center for Sexual Medicine and Department of Urology Inha University School of Medicine Incheon 400-711 Korea

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.

关键词： cell culture fibrosis histone deacetylase Peyronie＇s disease transforming growth factor-beta

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Astragaloside Ⅳ suppresses post-ischemic natural killer cell infiltration and activation in the brain:involvement of histone deacetylase inhibition

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Frontiers of Medicine 2021年第1期15卷 79-90页

作者： Baokai Dou Shichun Li Luyao Wei Lixin Wang Shiguo Zhu Zhengtao Wang Zunji Ke Kaixian Chen Zhifei Wang School of Basic Medical Sciences Shanghai University of Traditional Chinese MedicineShanghai 201203China Institute of Chinese Materia Medica Shanghai University of Traditional Chinese MedicineShanghai 201203China Academy of Integrative Medicine Shanghai University of Traditional Chinese MedicineShanghai 201203China

Natural killer(NK)cells,a type of cytotoxic lymphocytes,can infiltrate into ischemic brain and exacerbate neuronal cell death.Astragaloside Ⅳ(ASIV)is the major bioactive ingredient of Astragalus membranaceus,a Chinese herbal medicine,and possesses potent immunomodulatory and neuroprotective properties.This study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK cells.ASIV reduced brain infarction and alleviated functional deficits in MCAO rats,and these beneficial effects persisted for at least 7 days.Abundant NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia,and this infiltration was suppressed by ASIV.Strikingly,ASIV reversed NK cell deficiency in the spleen and blood after brain ischemia.ASIV inhibited astrocyte-derived CCL2 upregulation and reduced CCR2+NK cell levels in the ischemic brain.Meanwhile,ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γproduction.ASIV restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain,suggesting inhibition of histone deacetylase(HDAC).Simultaneously,ASIV prevented p65 nuclear translocation.The effects of ASIV on reducing CCL2 production,restoring acetylated p65 levels and preventing p65 nuclear translocation were mimicked by valproate,an HDAC inhibitor,in astrocytes subjected to oxygen-glucose deprivation.Our findings suggest that ASIV inhibits post-ischemic NK cell brain infiltration and activation and reverses NK cell deficiency in the periphery,which together contribute to the beneficial effects of ASIV against brain ischemia.Furthermore,ASIV’s effects on suppressing NK cell brain infiltration and activation may involve HDAC inhibition.

关键词： astragalosideⅣ brain ischemia natural killer cells histone deacetylase nuclear factor-κB

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Arabidopsis thaliana histone deacetylase1(AtHD1)is localized in euchromatic regions and demonstrates histone deacetylase activity in vitro

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Cell Research 2006年第5期16卷 479-488页

作者： Paulus M Fong Z Jeffrey Chen Department of Soil and Crop Sciences Texas A&M UniversityCollege StationTX 77843USA Molecular Cell and Developmental Biology University of Texas at AustinAustinTX78712USA

Arabidopsis thaliana histone deacetylase 1 (AtHD1 or AtHDA19),a homolog of yeast RPD3,is a global regulator ofmany physiological and developmental processes in plants.In spite of the genetic evidence for a role of AtHD1 in plantgene regulation and development,the biochemical and cellular properties of AtHD1 are poorly understood.Here we reportcellular localization patterns of AtHD1 in vivo and histone deacetylase activity in vitro.The transient and stable expres-sion of a green fluorescent protein (GFP)-tagged AtHD1 in onion cells and in roots,seeds and leaves of the transgenicArabidopsis,respectively,revealed that AtHD1 is localized in the nucleus presumably in the euchromatic regions andexcluded from the nucleolus.The localization patterns of AtHD1 are different from those of AtHD2 and AtHDA6 thatare involved in nucleolus formation and silencing of transgenes and repeated DNA elements,respectively.In addition,a histone deacetylase activity assay showed that the recombinant AtHD1 produced in bacteria demonstrated a specifichistone deacetylase activity in vitro.The data suggest that AtHD1 is a nuclear protein and possesses histone deacetylaseactivities responsible for global transcriptional regulation important to plant growth and development.

关键词： Arabidopsis histone deacetylase RPD3 subcellular localization gene silencing chromatin

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Expression of histone deacetylase (HDAC) family members in bortezomib-refractory multiple myeloma and modulation by panobinostat

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Cancer Drug Resistance 2021年第4期4卷 888-902页

作者： Tiewei Cheng Kendall Kiser Leslie Grasse Lakesla Iles Geoffrey Bartholomeusz Felipe Samaniego Robert Z.Orlowski Joya Chandra Department of Pediatrics Research University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Experimental Therapeutics University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Lymphoma and Myeloma University of Texas MD Anderson Cancer CenterHoustonTX 77030USA McGovern Medical School University of Texas Health Science Center at HoustonHoustonTX 77030USA Department of Epigenetics and Molecular Carcinogenesis University of Texas MD Anderson Cancer CenterHoustonTX 77030USA

Aim:Multiple myeloma(MM)is a hematological malignancy of antibody-producing mature B cells or plasma cells.The proteasome inhibitor,bortezomib,was the first-in-class compound to be FDA approved for MM and is frequently utilized in induction therapy.However,bortezomib refractory disease is a major clinical concern,and the efficacy of the pan-histone deacetylase inhibitor(HDACi),panobinostat,in bortezomib refractory disease indicates that HDAC targeting is a viable strategy.Here,we utilized isogenic bortezomib resistant models to profile HDAC expression and define baseline and HDACi-induced expression patterns of individual HDAC family members in sensitive vs.resistant cells to better understanding the potential for targeting these enzymes.Methods:Gene expression of HDAC family members in two sets of isogenic bortezomib sensitive or resistant myeloma cell lines was examined.These cell lines were subsequently treated with HDAC inhibitors:panobinostat or vorinostat,and HDAC expression was evaluated.CRISPR/Cas9 knockdown and pharmacological inhibition of specific HDAC family members were conducted.Results:Interestingly,HDAC6 and HDAC7 were significantly upregulated and downregulated,respectively,in bortezomib-resistant cells.Panobinostat was effective at inducing cell death in these lines and modulated HDAC expression in cell lines and patient samples.Knockdown of HDAC7 inhibited cell growth while pharmacologically inhibiting HDAC6 augmented cell death by panobinostat.Conclusion:Our data revealed heterogeneous expression of individual HDACs in bortezomib sensitive vs.resistant isogenic cell lines and patient samples treated with panobinostat.Cumulatively our findings highlight distinct roles for HDAC6 and HDAC7 in regulating cell death in the context of bortezomib resistance.

关键词： histone deacetylase bortezomib resistance selective HDAC inhibitors HDAC6 HDAC7

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Potential role of histone deacetylase 3 specific inhibitor Compound A in diabetes treatment

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中国药理学与毒理学杂志 2019年第10期 758-758页

作者： LEI Lei XIA Jie LIU Quan SUN Su-juan LIU Shuai-nan LI Cai-na CAO Hui HUAN Yi SHEN Zhu-fang The State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical College

OBJECTIVE In order to develop histone deacetylase 3(HDAC3) as a therapeutic target of diabetes,this project was mainly to study the antidiabetic potential role of HDAC3 specific inhibitor and its mechanism.METHODS HDAC3-selective inhibition small molecule Compound A was found through screening method in vitro.In vivo, the potency of Compound A on regulating blood glucose was test in streptozotocin(STZ) and high fat diet(HFD) induced diabetic mice, and hyperglycemic clamp technique was used to evaluate its effect on β cell function. At the same time, the ability of Compound A to promote insulin secretion was also assessed in β cells. RESULTS Compound A could down-regulate the fasting glycemia and ameliorate the oral glucose tolerance significantly. It could also augment the glucose infusion rate, and improve phaseⅠinsulin secretionand β cel function during the hyperglycemic clamp test. Besides, Compound A could promote insulin secretion in β cell line MIN6 cells, and up-regulate the expression level of Ins1 and Ins2. CONCLUSION HDAC3 specific inhibitor Compound A had the antidiabetic effect in STZ/HFD induced diabetic mice, which could be related to amelioration of β cell function. Furthermore,HDAC3 might be a novel drug target for diabetes treatment.

关键词： histone deacetylase diabetes β cell insulin

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