组蛋白去乙酰化酶抑制剂抗肿瘤的研究进展

核心组蛋白的乙酰化和去乙酰化与基因调控密切相关.组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACI)通过有效上调抑癌基因的表达、阻断肿瘤生长和诱导肿瘤细胞选择性凋亡来治疗肿瘤.近年来,HDACIs成为肿瘤靶向治疗的研究新热点,其对肿瘤细胞迁移、侵袭、转移的抑制作用和抗肿瘤血管生成作用也被证实.     

组蛋白去乙酰化酶及其抑制剂与妇科肿瘤

妇科肿瘤严重威胁着妇女的身心健康，非手术药物治疗亦存在许多问题。近年来，研究表明，组蛋白去乙酰化酶及其抑制剂与妇科肿瘤存在密切的联系，其作用及机制也是目前研究的热点，并是今后有望在妇科肿瘤治疗方面取得重大突破的方向。因此组蛋白去乙酰化酶及其抑制剂与妇科肿瘤的关系将作为本文的重点做一讨论。     

组蛋白去乙酰化酶及其抑制剂与妇科肿瘤

妇科肿瘤严重威胁着妇女的身心健康,非手术药物治疗亦存在许多问题.近年来,研究表明,组蛋白去乙酰化酶及其抑制剂与妇科肿瘤存在密切的联系,其作用及机制也是目前研究的热点,并是今后有望在妇科肿瘤治疗方面取得重大突破的方向.因此组蛋白去乙酰化酶及其抑制剂与妇科肿瘤的关系将作为本文的重点做一讨论.     

组蛋白去乙酰化酶9在肿瘤中的作用

组蛋白去乙酰化酶9（histone deacetylase 9,HDAC9）属于组蛋白去乙酰化酶（histone deacetylases,HDACs）Ⅱa亚型,在体内通过催化组蛋白3（H3）、组蛋白4（H4）和非组蛋白的去乙酰化,改变染色体的结构,调节基因的转录。研究表明HDAC9表达异常与肿瘤关系密切,但不同肿瘤中HDAC9的表达和功能不同,最终造成促癌或抑癌的相反结果,具体机制尚不明确。当前利用组蛋白去乙酰化酶抑制剂（histone deacetylases inhibitors,HDACIs）的表观遗传治疗已成为热点,研制特异性HDACIs并与化疗、放疗以及免疫治疗相结合已成为未来的方向,但靶向针对HDAC9的治疗研究非常有限。本文就HDAC9在肿瘤中的作用进行综述。      

组蛋白去乙酰化酶及其抑制剂在骨肉瘤分子机制中的作用研究进展

骨肉瘤 ( osteosarcoma,OS ) 起源于间叶细胞,是一种最常见于 10～30 岁青少年的原发恶性骨肿瘤,多见于长骨干骺端,具有侵袭性强且易转移等特点 [1-4].目前主要的治疗包括手术结合新辅助化疗,但是存在耐药、转移、复发等问题 [5-6].已发生肺部等远处转移的骨肉瘤患者几乎不可治愈,5 年总体生存率...     

组蛋白去乙酰化酶抑制剂在非霍奇金淋巴瘤中的研究进展

组蛋白去乙酰化酶（HDAC）是一种可以调控基因表达、修饰染色体结构的蛋白酶。在维持细胞的正常功能和调控基因表达的过程中,组蛋白乙酰化和去乙酰化水平的平衡起着重要作用。 HDAC过度表达并被转录因子募集,抑制某些基因的表达,导致肿瘤和其他疾病的发生和发展。近年来,随着对肿瘤表观遗传学研究的深入,HDAC 抑制剂在肿瘤发生、发展中的作用越来越引起研究者的重视。 HDAC抑制剂具有广泛的抗肿瘤活性,尤其在恶性血液病的治疗中,临床应用日益广泛。目前已有几种 HDAC抑制剂被用于非霍奇金淋巴瘤的治疗和临床研究,如伏立诺他、贝利司他、西达本胺、CUDC-907等。文章就以上 HDAC 抑制剂针对 NHL 的临床研究进展进行阐述。     

组蛋白乙酰化/去乙酰化与白血病的研究进展

组蛋白乙酰化/去乙酰化与基因调控密切相关.组蛋白乙酰化水平的异常在白血病的发展、增殖和分化中起着很重要的作用.随着对组蛋白乙酰化的深入研究,组蛋白去乙酰化酶抑制剂在白血病中的作用机制越来越受到人们的关注.     

组蛋白去乙酰化酶抑制剂治疗乳腺癌的临床研究

组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitors,HDACIs）作为第一个成功用于癌症治疗的表观遗传学相关药物,能够有效解除对抑癌基因转录的阻滞,已成为极具潜力的抗癌药物。近年来,HDACIs在乳腺癌治疗领域中的临床研究逐渐开展,已有个别HDACIs在大型临床研究中表现出较强的抗癌活性。本文针对HDACIs在乳腺癌治疗领域开展的临床研究作一综述,有利于临床医师更好的了解HDACIs在乳腺癌治疗中的现状与进展。     

组蛋白去乙酰化酶及其抑制剂与结直肠癌的关系

组蛋白乙酰化、去乙酰化修饰影响到染色质重塑,在基因表达的表观遗传调控中扮演重要角色。结直肠癌是临床上最常见的恶性肿瘤之一,是我国第二高发的肿瘤,研究证实结直肠癌的发生发展与组蛋白去乙酰化酶（ｈｉｓｔｏｎｅ ｄｅａｃｅｔｙｌａｓｅｓ,ＨＤＡＣｓ）异常密切相关,ＨＤＡＣ抑制剂（ＨＤＡＣｉｎｈｉｂｉｔｏｒ,ＨＤＡＣｉ）靶向ＨＤＡＣｓ,大量研究已证实ＨＤＡＣｉ单用或联合其他药物对结直肠癌细胞具有诱导分化、促进凋亡等作用,并能提高结直肠癌细胞对化疗药物的敏感性,提示ＨＤＡＣ靶向治疗结直肠癌可能是今后又一个新的发展方向。     

组蛋白去乙酰化酶抑制剂对神经胶质瘤的作用研究

正常细胞的分化以及代谢行为的调节依赖组蛋白乙酰基转移酶和组蛋白去乙酰化酶之间的平衡。一旦这种平衡关系被打破,细胞或组织就容易发生癌变,神经胶质瘤也不例外。神经胶质瘤是一种恶性度高且预后极差的颅内肿瘤,其作用机制尚不明确且呈浸润性生长。因此在治疗手段方面尚无行之有效的方法。组蛋白去乙酰化酶抑制剂作为一种新型的化疗药物为胶质瘤的治疗提供了新的方向。它通过阻碍细胞周期、诱导细胞分化和凋亡以及抑制肿瘤血管生成来抑制神经胶质瘤的生长和增殖。本文旨在从化学结构特点和对神经胶质瘤作用机制两方面阐述组蛋白去乙酰化酶抑制剂．并对新的一类组蛋白去乙酰化酶抑制剂丙戊酸及其衍生物的研究作一综述．     

Novel Chemotherapy using Histone Deacetylase Inhibitors in Cervical Cancer

Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes andpromotion of tumorigenesis in cervical cancers, novel compounds endowed with a histone deacetylase (HDAC)inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeuticeffects of HDAC inhibitors (HDACIs) in treating cervical cancer. HDACIs were able to mediate inhibition ofcell growth, cell cycle arrest, apoptosis, and the expression of genes related to the malignant phenotype in avariety of cervical cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylatedhistones in the chromatin of the p21WAF1 gene in human cervical carcinoma cells. In xenograft models, someHDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate thatHDACI drugs provide an important class of new mechanism-based therapeutics for cervical cancer. In thisreview, we discuss the biologic and therapeutic effects of HDACIs in treating cervical cancer, especially focusingon preclinical studies and clinical trials.     

A Rationally Designed Histone Deacetylase Inhibitor with Distinct Antitumor Activity against Ovarian Cancer

Histone deacetylase inhibitors (HDACIs) are a class of antineoplastic agents previously demonstrating preclinical chemosensitizing activity against drug-resistant cancer cells and mouse xenografts. However, whereas clinical studies have shown efficacy against human hematologic malignancies, solid tumor trials have proved disappointing. We previously developed a novel HDACI, “OSU-HDAC42,” and herein examine its activity against ovarian cancer cell lines and xenografts. OSU-HDAC42, (i) unlike most HDACIs, elicited a more than five-fold increase in G₂-phase cells, at 2.5 µM, with G₂ arrest followed by apoptosis; (ii) at 1.0 µM, completely repressed messenger RNA expression of the cell cycle progression gene cdc2; (iii) at low doses (0.25–1.0 µM for 24 hours), induced tumor cell epithelial differentiation, as evidenced by morphology changes and a more than five-fold up-regulation of epithelium-specific cytokeratins; (iv) potently abrogated the growth of numerous ovarian cancer cells, with IC₅₀ values of 0.5 to 1.0 µM, whereas also remaining eight-fold less toxic (IC₅₀ of 8.6 µM) to normal ovarian surface epithelial cells; and (v) chemosensitizated platinum-resistant mouse xenografts to cisplatin. Compared with the clinically approved HDACI suberoylanilide hydroxamic acid (vorinostat), 1.0 µM OSU-HDAC42 was more biochemically potent (i.e., enzyme-inhibitory), as suggested by greater gene up-regulation and acetylation of both histone and nonhistone proteins. In p53-dysfunctional cells, however, OSU-HDAC42 was two- to eight-fold less inductive of p53-regulated genes, whereas also having a two-fold higher IC₅₀ than p53-functional cells, demonstrating some interaction with p53 tumor-suppressive cascades. These findings establish OSU-HDAC42 as a promising therapeutic agent for drug-resistant ovarian cancer and justify its further investigation.     

组蛋白乙酰化抑制剂及其在甲状腺癌治疗中的应用

0 引言 甲状腺癌是内分泌系统常见的肿瘤,死亡率在内分泌系统肿瘤中居首位~([1]).目前研究发现,在甲状腺癌的发病机制中,染色体的重排及基因表达的异常调控起着重要作用.组蛋白尾部可逆的转录后修饰是基因调控表观遗传学的根本机制之一,各种不同的组蛋白尾部的修饰,能单独或协同构成特定形式的基因表达密码~([2]).     

组蛋白去乙酰化酶抑制剂诱导脑胶质瘤细胞凋亡及其机制的研究

背景与目的:使用分子靶向药物治疗胶质瘤是神经肿瘤领域的研究热点。本文探讨组蛋白去乙酰化酶抑制剂MS-275对脑胶质瘤细胞株U251细胞增殖和迁移的影响及其机制。方法:以不同药物浓度梯度与U251细胞分别共培养24、48和72h后,应用CCK-8法检测肿瘤细胞增殖,Transwell法检测药物作用前后U251细胞迁移能力的变化,Annexin V-FITC/PI法经流式检测细胞凋亡率,实时定量PCR检测IκB-α的RNA含量,免疫印迹检测IκB-α蛋白、磷酸化IκB-α蛋白和聚ADP核糖聚合酶(PARP)表达。结果:MS-275能显著抑制U251细胞的增殖。MS-275药物浓度40nmol/mL,与U251共培养72h,细胞增殖抑制率为(79.0±1.7)%;经药物作用72h后,U251细胞凋亡率为(29.000±2.306)%;实时定量PCR检测IκB-α的RNA含量随药物作用时间的延长而降低,免疫印迹检测提示IκB-α蛋白表达水平降低,IκB-α蛋白磷酸化被抑制,PARP被剪切。结论:MS-275对胶质瘤细胞的增殖和迁移抑制作用具有浓度和时间依赖性,其机制是通过抑制IκB-α蛋白磷酸化诱导凋亡实现的。     

The Emerging Role of Histone Deacetylase Inhibitors in Treating T-cell Lymphomas

T-cell lymphomas are an uncommon and heterogeneous group of non-Hodgkin lymphomas. Historically, therapies for these diseases have been borrowed from treatments for other lymphomas. More recently, efforts have be made to identify novel agents for their activity specifically in T-cell lymphomas. A primary example of new agents with specific activity in T-cell lymphomas is the novel class of drug, histone deacetylase inhibitors. The potential activity of histone deacetylase inhibitors was discovered somewhat serendipitously, but these early discoveries were followed by some larger and more rigorous studies in T-cell lymphomas. Two compounds, vorinostat and romidepsin, are currently approved and are in clinical use for the treatment of cutaneous T-cell lymphomas. Other drugs are in development, and a large study of romidepsin in peripheral T-cell lymphoma has recently been completed. This review covers data on the use of histone deacetylase inhibitors in T-cell lymphomas, as well as early attempts, just beginning, to combine these agents with other novel therapies.     

Expression Profile of Histone Deacetylase 1 in Gastric Cancer Tissues

Although histone deacetylases (HDACs) appear to play a crucial role in carcinogenesis, the expression status of HDACs in primary human cancer tissues has not yet been reported. In this study, we investigated the expression level of HDAC1 in 25 paired primary human gastric cancer (GC) tissues and corresponding normal tissues through semi-quantitative RT-PCR and immunoblot analysis. The HDAC1 expression pattern was also topologically examined through immunohisto-chemistry. Overexpression of HDAC1 mRNA was detected in 68% of GC tissues (17 of 25), and the relative density of HDAC1 mRNA in GC tissue was increased 1.8-fold versus the normal counterpart (P<0.01). Elevated expression of HDAC1 protein was also detected in 61% of GC samples (11 of 18), which also showed an increased mRNA level of HDAC. Immunohistochemically, overexpression of HDAC1 was predominantly localized in the nuclei of most neoplastic cells, including embolic tumor cells, whereas normal glandular epithelial cells revealed only weak HDAC1 expression that was focal in distribution. Thus, the present study clearly demonstrates that HDAC1 is overexpressed in GC and probably plays a significant role in gastric carcinogenesis.     

Identification of Histone Deacetylase 1 Protein Complexes inLiver Cancer Cells

Background: Hepatocellular carcinoma is one of the leading causes of mortalities worldwide. The searchfor new therapeutic targets is of utmost importance for improved treatment. Altered expression of HDAC1 inhepatocellular carcinoma (HCC) and its requirement for liver formation in zebrafish, suggest that it may regulatekey events in liver carcinogenesis and organogenesis. However, molecular mechanisms of HDAC1 action in livercarcinogenesis are largely unknown. The present study was conducted to identify HDAC1 interacting proteinsin HepG2 cells using modified SH-double-affinity purification coupled with liquid mass spectrophotemetery.Materials and Methods: HepG2 cells were transfected with a construct containing HDAC1 with a C-terminalstrepIII-HA tag as bait. Bait proteins were confirmed to be expressed in HepG2 cells by western blotting andpurified by double affinity columns and protein complexes for analysis on a Thermo LTQ Orbitrap XL using a C18nano flow ESI liquid chromatography system. Results: There were 27 proteins which showed novel interactionswith HDAC1 identified only in this study, while 14 were among the established interactors. Various subunits ofT complex proteins (TCP1) and prefoldin proteins (PFDN) were identified as interacting partners that showedhigh affinity with HDAC1 in HepG2 cells. Conclusions: The double affinity purification method adopted in thisstudy was very successful in terms of specificity and reproducibility. The novel HDAC1 complex identified inthis study could be better therapeutic target for treatment of hepatocellular carcinoma.