组蛋白去乙酰化酶抑制剂的研究进展

核小体是真核生物染色质的基本单位,通过对组蛋白核心的N-端的乙酰化、甲基化、磷酸化、遍在蛋白化的修饰作用而影响细胞的功能。组蛋白乙酰化酶(histone acetylase HAT)及组蛋白去乙酰化酶(Histone Deacetylases HDAC)之间的动态平衡控制着染色质的结构和基因表达。当组蛋白去乙酰化水平增加,乙酰化水平相对降低,即会导致正常的细胞周期与代谢行为的改变而诱发肿瘤,及神经退行性变。组蛋白去乙酰化酶抑制剂(Histone Deacetylases-inhibitor HDACi)目前是国内外研究的热点。其中,曲古霉素A(Trichostatin A TSA),是最早发现的天然组蛋白去乙酰化酶抑制剂;伏立诺他(Suberoylanilide Hydroxamic Acid SAHA)已经美国FDA批准用于治疗皮肤T细胞淋巴瘤。本文就HDACi分类及其功能出发综述HDACi的作用机制及研究进展。     

组蛋白去乙酰化酶11的免疫调控功能及其在免疫相关疾病中的作用研究进展

组蛋白乙酰化是一种重要的表观遗传修饰,受到组蛋白乙酰转移酶和组蛋白去乙酰化酶的动态调节。组蛋白去乙酰化酶11 (histone deacetylases 11, HDAC11)是IV类HDAC的唯一成员,能够催化组蛋白和非组蛋白赖氨酸残基去乙酰化并具有去脂酰化活性。HDAC11与免疫细胞的成熟、分化和功能密切相关,多数研究显示HDAC11通过负调控IL-10和上调促炎细胞因子发挥免疫激活作用,但HDAC11也负调控中性粒细胞和T细胞的功能,发挥免疫抑制作用。最近报道HDAC11在炎症反应、肿瘤免疫、移植免疫、自身免疫疾病中发挥重要作用,是免疫治疗的重要靶点。该文就HDAC11的生物学特性、免疫调控功能、在免疫相关性疾病中的作用及其抑制剂开发的最新研究进展作一综述。     

组蛋白去乙酰化酶1/2参与调控小鼠卵子发生的研究进展

卵子发生是雌性哺乳动物的基本生殖过程,是后续受精及胚胎发育的基础.近年来研究表明,表观修饰在调控哺乳动物生殖过程(如卵子发生、精子发生、植入前胚胎发育及性别分化等)中扮演着重要的角色.以组蛋白乙酰化为例,组蛋白乙酰转移酶(histone acetyltransferases,HATs)和去乙酰化酶(histone de...     

组蛋白去乙酰化酶抑制剂的研究进展

组蛋白是真核生物核染色体的重要组成部分。它们被分为五类(H,H2A,H2B,H3和H4),两组:核心组蛋白(H2A,H2B,H3和H4)和联结子组蛋白(H1)[1]。由组蛋白修饰所造成的染色体局部构象的改变,在真核生物基因表达调控中发挥着举足轻重的作用[2]。     

组蛋白乙酰化/去乙酰化在真核基因转录调控中的作用

真核生物中 ,染色质的基本单位是核小体。核小体由H2 A ,H2 B ,H3 ,H4构成的核心组蛋白八聚体及缠绕于其上的DNA构成。最近的研究结果表明 ,核心组蛋白的乙酰化 去乙酰化过程是调控基因活性的一个关键步骤[1] 。而含有组蛋白去乙酰化酶活性的分子有两类 :一类是与酵母RPD3同源的分子 ,另一类是与RPD3不同源的分子。它们各有其不同的来源 ,存在于各自的复合物中 ,催化不完全相同的组蛋白或其他蛋白质去乙酰化 ;这些去乙酰化酶与基因转录的调控存在着密切的关系 ,主要是介导基因转录的抑制。     

神经退行性疾病中的乙酰化内稳态

近年来对神经退行性疾病机制的研究发现,乙酰化和去乙酰化在这一过程扮演了重要角色。组蛋白乙酰化酶(histone acetylase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)两大家族分别催化组蛋白的乙酰化和去乙酰化,两者相互拮抗,维持体内乙酰化内稳态的平衡。乙酰化内稳态的概念就是在这样的基础上提出的。在神经退行性疾病的发病过程中,组蛋白乙酰基转移酶含量下降,乙酰化内稳态被打破,影响了神经细胞内重要基因的转录,从而导致了神经细胞功能失调甚至死亡。该文主要介绍HAT和HDAC两大家族在神经退行性疾病中的作用机制,以及针对乙酰化内稳态平衡机制的治疗策略。     

组蛋白去乙酰化酶抑制剂在急性髓系白血病中的应用

急性髓系白血病（AML）是造血干/祖细胞恶性克隆性疾病,以骨髓、血液和其他组织中髓系起源的异常原始细胞增殖为特征。“3+7”诱导方案（蒽环类药物联合阿糖胞苷）一直是治疗AML的基石,但仍有部分AML患者无法耐受强化疗或完全缓解后复发,目前AML的总体疗效仍不乐观。因此,寻找新药物以提高AML患者疗效具有重要的临床意义。越来越多的研究证明,表观遗传对AML的发生、发展起重要作用。组蛋白去乙酰化酶抑制剂（HDACi）是表观遗传修饰的分子靶向药物,可抑制组蛋白去乙酰化酶（HDAC）的活性,上调组蛋白赖氨酸的乙酰化水平,目前已应用于AML临床研究中,在联合治疗中显现出良好的耐受性与治疗效果。本综述介绍了HDAC和HDACi的分类依据以及在临床上的应用,阐述了伏立诺他、贝利司他、帕比司他、戊丙酸、恩替诺特、西达本胺等6种HDACi在AML中的临床前研究结果和临床应用研究进展,讨论了HDACi与其他抗癌药物联用在AML中的作用机制,并对HDACi今后的发展提出了建议,期望为临床治疗AML提供参考。     

组蛋白乙酰化／去乙酰化作用与真核基因转录调控

核小体组蛋白的翻译后修饰是真核基因转录调控中的关键步骤。对于组蛋白的这类修饰方式 ,近年来研究最为活跃的是组蛋白Ｎ末端区域保守的Ｌｙｓ上ε ＮＨ 3 的乙酰化作用。随着各种组蛋白乙酰化酶 /去乙酰化酶被克隆、鉴定 ,组蛋白乙酰化 /去乙酰化作用与真核基因转录调控之间的关系也开始逐步得以阐明。1 .真核转录相关的组蛋白乙酰化酶和组蛋白去乙酰化酶1 .1　组蛋白乙酰化酶 (ｈｉｓｔｏｎｅａｃｅｔｙｌｔｒａｎｓ ｆｅｒａｓｅ ,ＨＡＴ)　　核小体组蛋白中Ｎ末端区域上保守的Ｌｙｓ的乙酰化是染色质具有转录活性的标志之一。在组蛋白…     

Nucleostemin和HDAC1在卵巢肿瘤中的表达及意义

目的:研究核干细胞因子(Nucleostemin, NS)和组蛋白去乙酰化酶1(HDAC1)在卵巢肿瘤及正常卵巢组织中的表达,并分析其表达与临床指标的关系及两者间的表达相关性。方法:选择2010年至2017年我院卵巢石蜡标本60例,其中卵巢肿瘤50例,正常卵巢组织10例。应用免疫组化法检测NS与HDAC1的表达,并分析它们与年龄、肿瘤分期等临床指标的相关性。结果:在30例卵巢恶性肿瘤、10例卵巢交界性肿瘤、10例卵巢良性肿瘤组织中,NS表达的阳性率分别为93.3%、40%、20%,HDAC1的阳性率分别为90%、60%、20%。在正常卵巢组织中未见NS及HDAC1表达。在卵巢恶性肿瘤组中,NS和HDAC1的阳性表达率显著高于其他三组(P0.05),两者表达呈正相关(r=0.56, P0.05),且均与分化程度呈负相关(r=-0.76, P0.001; r=-0.53, P0.01),而与患者年龄、术前血清CA125水平、临床分期和病理类型无关。结论:NS和HDAC1倾向于卵巢恶性肿瘤中表达,且与卵巢恶性肿瘤的分化程度负相关。     

沉默交配型信息调节因子2同源蛋白Sirt1

沉默交配型信息调节因子2同源蛋白1(silent mating type information regulation 2 homolog 1,Sirt1)是哺乳动物中与酵母沉默信息调节蛋白2(silencing information regulator 2,Sir2)高度同源的蛋白质,它是一种依赖NAD+的III类组蛋白去乙酰化酶(HDAC III),在细胞分化、衰老、凋亡、DNA损伤修复、能量及内分泌代谢调节中起重要作用,同时在基因沉默、表观遗传学修饰、转录调控及信号转导调节中发挥重要的生物学功能。本文对其近年的研究进展做一概述。     

Sirt1与生物钟的相互调控

生物钟调控机制广泛存在于各种类型的细胞中,控制着细胞代谢的节律性变化.最近的研究发现,NAD+依赖的组蛋白去乙酰化酶Sirt1参与了生物钟调控过程,对维持正常的生物钟节律具有重要作用;另一方面,Sirt1的表达也受到生物钟系统的调控,呈现出昼夜节律性的表达.因此Sirt1能与生物钟进行相互调控,并且这一作用机制很可能广泛参与了不同类型细胞内的信号转导和能量代谢过程.本文总结了Sirt1与生物钟之间相互调控的一些研究进展,对它们之间的分子调控机制进行了概述.     

Sirt1及其相关信号通路蛋白调节胰岛素敏感性的研究进展

Sirt1是哺乳动物长寿基因Sir2的同源蛋白,越来越多研究表明Sirt1在糖脂代谢和胰岛素敏感性调节中起重要作用。Sirt1具有NAD依赖的去乙酰化酶的作用,可通过一系列底物去乙酰化,参与调节胰岛素敏感性。它通过影响胰岛素敏感性密切相关的信号蛋白,包括PGC-1α、PPARγ、PTP1B、NFκB/JNK等,影响其下游信号分子的表达或活性,调节糖脂代谢,抑制脂肪组织低级炎症,进而对胰岛素敏感性起着重要的调节作用。Sirt1还通过NAD+水平与AMPK相互调节,维持细胞的能量平衡。Sirt1可能成为改善胰岛素抵抗潜在的药物作用靶点。     

Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation

Emerging proteomic evidence suggests that acetylation of metabolic enzymes is a prevalent post-translational modification. In a few recent reports, acetylation down-regulated activity of specific enzymes in fatty acid oxidation, urea cycle, electron transport, and anti-oxidant pathways. Here, we reveal that the glycolytic enzyme phosphoglycerate mutase-1 (PGAM1) is negatively regulated by Sirt1, a member of the NAD(+)-dependent protein deacetylases. Acetylated PGAM1 displays enhanced activity, although Sirt1-mediated deacetylation reduces activity. Acetylation sites mapped to the C-terminal "cap," a region previously known to affect catalytic efficiency. Overexpression of a constitutively active variant (acetylated mimic) of PGAM1 stimulated flux through glycolysis. Under glucose restriction, Sirt1 levels dramatically increased, leading to PGAM1 deacetylation and attenuated activity. Previously, Sirt1 has been implicated in the adaptation from glucose to fat burning. This study (i) demonstrates that protein acetylation can stimulate metabolic enzymes, (ii) provides biochemical evidence that glycolysis is modulated by reversible acetylation, and (iii) demonstrates that PGAM1 deacetylation and activity are directly controlled by Sirt1.     

Sirt7在病理生理活动中的作用机制

沉默信息调节因子2相关酶(silent mating type information regulator 2-related enzymes,Sirtuin)是烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide,NAD⁺)依赖性的去乙酰化酶。Sirt7是定位于核仁的Sirtuin蛋白家族成员,除了具有去乙酰化酶活性外,还具有腺苷二磷酸(adenosine diphosphate,ADP)-核糖基转移酶、去琥珀酰化酶和去戊二酰化酶活性。Sirt7的作用底物包括组蛋白、DNA损伤修复相关因子、核仁小核糖核蛋白成分(核仁纤维蛋白、U3)、转录因子(GA结合蛋白β1(GA binding protein β1,GABPβ1)、叉头框蛋白O4、GATA4)、细胞周期蛋白依赖激酶9、组蛋白乙酰转移酶1、聚合酶相关因子53(polymerase associated factor 53,PAF53)、Ras相关核蛋白(Ras-related nuclear protein,Ran)、活化T细胞的核因子c1和p53等。另外,Sirt7还可以与损伤特异性DNA结合蛋白1(damage-specific DNA binding protein 1,DDB1)/cullin 4/DDB1-cullin 4相关因子1、Suv39h1/Sirt1、Myc、核呼吸因子1和Elk4等作用,进而调节其功能,但作用机制尚不清楚。Sirt7的多种活性使其在维持基因组稳定、调节RNA转录、抵御应激反应、调控代谢及炎症等病理生理活动中发挥重要作用。本文将介绍Sirt7在调节以上病理/生理活动中的作用机制,以及腺苷酸活化蛋白激酶(adenosine 5′-monophosphate activated protein kinase,AMPK)、蛋白质精氨酸甲基转移酶6、泛素特异性肽酶7等对Sirt7蛋白合成及活性的调节作用,并对目前Sirt7研究中存在的问题进行讨论。     

The Role of Sirt1 in Bile Acid Regulation during Calorie Restriction in Mice

Sirtuin 1 (Sirt1) is an NAD⁺-dependent protein deacetylase that is proposed to mediate many health-promoting effects of calorie restriction (CR). We recently reported that short-term CR increased the bile acid (BA) pool size in mice, likely due to increased BA synthesis in liver. Given the important role of Sirt1 in the regulation of glucose, lipid, as well as BA metabolism, we hypothesized that the CR-induced increase in BAs is Sirt1-dependent. To address this, the present study utilized genetically-modified mice that were Sirt1 loss of function (liver knockout, LKO) or Sirt1 gain of function (whole body-transgenic, TG). Three genotypes of mice (Sirt1-LKO, wild-type, and Sirt1-TG) were each randomly divided into ad libitum or 40% CR feeding for one month. BAs were extracted from various compartments of the enterohepatic circulation, followed by BA profiling by UPLC-MS/MS. CR increased the BA pool size and total BAs in serum, gallbladder, and small intestine. The CR-induced increase in BA pool size correlated with the tendency of increase in the expression of the rate-limiting BA-synthetic enzyme Cyp7a1. However, in contrast to the hypothesis, the CR-induced increase in BA pool size and Cyp7a1 expression was still observed with ablated expression of Sirt1 in liver, and completely suppressed with whole-body overexpression of Sirt1. Furthermore, in terms of BA composition, CR increased the ratio of 12α-hydroxylated BAs regardless of Sirt1 genotypes. In conclusion, the CR-induced alterations in BA pool size, BA profiles, and expression of BA-related genes do not appear to be dependent on Sirt1.     

Pharmacological Activation of Sirt1 Ameliorates Polyglutamine-Induced Toxicity through the Regulation of Autophagy

Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington’s disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, β-lapachone (β-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with β-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a pathogenic polyQ stretch fused to green fluorescent protein (HttEx1(97Q)-GFP). β-lap increased autophagy in SH-SY5Y cells, as evidenced by the increased formation of LC3-II and autolysosomes. Furthermore, β-lap reduced HttEx1(97Q)-GFP aggregation, which was significantly prevented by co-incubation with 3-methyladenine, an inhibitor of autophagy. β-lap increased Sirt1 activity, as shown by the increased deacetylation of the Sirt1 substrates, PARP-1 and Atg5, and the nuclear translocation of FOXO1. Both the induction of autophagy and attenuation of HttEx1(97Q)-GFP aggregation by β-lap were significantly prevented by co-incubation with sirtinol, a general sirtuin inhibitor or by co-transfection with shRNA against Sirt1. The pro-autophagic actions of β-lap were further investigated in a transgenic Caenorhabditis elegans (C. elegans) line that expressed Q67 fused to cyanine fluorescent protein (Q67). Notably, β-lap reduced the number of Q67 puncta and restored Q67-induced defects in motility, which were largely prevented by pre-treatment with RNAi against sir-2.1, the C. elegans orthologue of Sirt1. Collectively, these data suggest that β-lap induces autophagy through activation of Sirt1, which in turn leads to a reduction in polyQ aggregation and cellular toxicity. Thus, β-lap provides a novel therapeutic opportunity for the treatment of HD.     

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

Sirtuins regulate a variety of cellular processes through protein deacetylation. The best-known member of mammalian sirtuin family, Sirt1, plays important roles in the maintenance of cellular homeostasis by regulating cell metabolism, differentiation and stress responses, among others. Sirt1 activity requires tight regulation to meet specific cellular requirements, which is achieved at different levels and by specific mechanisms. Recently, a regulatory loop between Sirt1 and another sirtuin, Sirt7, was identified. Sirt7 inhibits Sirt1 autodeacetylation at K230 and activation thereby preventing Sirt1-mediated repression of adipocyte differentiation by inhibition of the PPARγ gene. Here, we extend the regulatory complexity of Sirt7-dependent restriction of Sirt1 activity by demonstrating that Sirt7 reduces activation of a previously described prominent Sirt1 target, the histone methyltransferase Suv39h1. We show that removal of the acetyl-group at K230 in Sirt1 due to the absence of Sirt7 leads to hyperactivation of Sirt1 and thereby to constantly increased activity of Suv39h1.     

HIF-1alpha信号通路在肿瘤细胞调控中的研究进展

缺氧诱导因子（HIF-1alpha）是肿瘤细胞生长过程中重要的调控因子,研究其作用机制有利于实现对肿瘤细胞增殖的抑制作用。 HIF-1alpha可引起多种基因转录,使肿瘤细胞耐受低氧环境,进而使癌症患者在治疗过程中产生耐受反应,最终影响治疗效果,甚至 放弃治疗。因此,以HIF-1alpha为靶点是治疗肿瘤的重要手段和方法。本文对HIF-1alpha的基本概况及其主要信号通路（PI3K 通路、 HSP90 通路及MAPK通路）以及不同通路抑制剂（如LY294002、17AAG、PD98059、U0126、SB203580、SP600125 等）进行综述,并 对HIF-1alpha的应用前景进行展望。