• 【DNA甲基转移酶抑制剂及其在癌症表观遗传治疗中的新兴作用。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Gnyszka A,Jastrzebski Z,Flis S
    BACKGROUND & AIMS: :The DNA methyltransferase (DNMT) inhibitors azacytidine and decitabine are the most successful epigenetic drugs to date and are still the most widely used as epigenetic modulators, even though their application for oncological diseases is restricted by their relative toxicity and poor chemical stability. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one), a more stable and less toxic cytidine analog, is another inhibitor of DNMT with concomitant inhibitory activity towards cytidine deaminase. Unfortunately, there is no new information related to the possible clinical applications of zebularine. Although many new inhibitors of DNMT have been identified, none of them can so far replace azacytidine, decitabine and, to a lesser degree, zebularine. This review summarizes the current data and knowledge about azacytidine, decitabine and zebularine, and their role in present and possible future epigenetic cancer therapy. We also discuss the molecular modes of action of these agents with consideration of their different toxicities and demethylation profiles, reflecting their complex and partially overlapping biological effects.
    背景与目标: :DNA甲基转移酶(DNMT)抑制剂氮胞苷和地西他滨是迄今为止最成功的表观遗传药物,尽管它们在肿瘤疾病中的应用受到相对毒性和化学稳定性的限制,但它们仍然是表观遗传调节剂最广泛的应用。 Zebularine(1-(β-D-呋喃核糖基)-1,2-二氢嘧啶-2-一)是一种更稳定,毒性较小的胞苷类似物,是DNMT的另一种抑制剂,具有对胞苷脱氨酶的抑制活性。不幸的是,没有与zebularine的可能临床应用有关的新信息。尽管已鉴定出许多新的DNMT抑制剂,但迄今为止,它们均无法替代氮杂胞苷,地西他滨,甚至在较小程度上可替代zebularine。这篇综述总结了关于氮杂胞苷,地西他滨和zebularine的最新数据和知识,以及它们在当前和未来可能的表观遗传学癌症治疗中的作用。我们还讨论了这些试剂的分子作用方式,并考虑了它们的不同毒性和脱甲基特性,反映了它们复杂且部分重叠的生物学效应。
  • 2 Epigenetic regulation of EMT: the Snail story. 复制标题 收藏 收藏

    【EMT的表观遗传调控:蜗牛的故事。】 复制标题 收藏 收藏
    DOI:10.2174/13816128113199990512 复制DOI
    作者列表:Lin Y,Dong C,Zhou BP
    BACKGROUND & AIMS: :While the epithelial-mesenchymal transition (EMT) plays a fundamental role during development, its deregulation can adversely promote tumor metastasis. The phenotypic and cellular plasticity of EMT indicates that it is subject to epigenetic regulation. A hallmark of EMT is E-cadherin suppression. In this review, we try to embrace recent findings on the transcription factor Snail-mediated epigenetic silencing of E-cadherin. Our studies as well as those of others independently demonstrated that Snail can recruit various epigenetic machineries to the E-cadherin promoter. Based on these results, we propose a model of epigenetic regulation of EMT governed by Snail. Briefly, recruitment of the LSD1/HDAC complex by Snail facilitates histone H3K4 demethylation and H3/H4 deacetylation. Histone deacetylation may promote subsequent recruitment of PRC2 to methylate H3K27, while H3K4 demethylation favors the association of H3K9 methyltransferases G9a and Suv39H1. Finally, DNA methyltransferases (DNMTs) can be recruited to the promoter area in a G9a/Suv39H1-dependent manner. Together, these chromatin-modifying enzymes function in a Snail-mediated, highly orchestrated fashion to suppress E-cadherin. Disruption of the connection between Snail and these epigenetic machineries may represent an efficient strategy for the treatment of EMT-related diseases, including tumor metastasis.
    背景与目标: :尽管上皮-间质转化(EMT)在发育过程中起着基本作用,但其失调会不利地促进肿瘤转移。 EMT的表型和细胞可塑性表明它受到表观遗传调控。 EMT的标志是抑制E-钙黏着蛋白。在这篇综述中,我们尝试包含关于转录因子Snail介导的E-cadherin沉默的最新发现。我们的研究以及其他人的研究独立证明,Snail可以为E-cadherin启动子募集各种表观遗传机制。基于这些结果,我们提出了由Snail控制的EMT的表观遗传调控模型。简而言之,通过Snail募集LSD1 / HDAC复合物有助于组蛋白H3K4脱甲基和H3 / H4脱乙酰。组蛋白去乙酰化可能促进随后募集PRC2来甲基化H3K27,而H3K4去甲基化则有利于H3K9甲基转移酶G9a和Suv39H1的缔合。最后,可以以G9a / Suv39H1依赖的方式将DNA甲基转移酶(DNMT)募集到启动子区域。这些染色质修饰酶一起以Snail介导的,高度协调的方式发挥功能,以抑制E-钙黏着蛋白。破坏Snail和这些表观遗传机制之间的联系可能代表一种有效的策略,用于治疗EMT相关疾病,包括肿瘤转移。
  • 【肿瘤免疫微环境的表观遗传调控,以增强免疫检查站封锁疗法。】 复制标题 收藏 收藏
    DOI:10.1158/2159-8290.CD-19-1349 复制DOI
    作者列表:Menzel J,Black JC
    BACKGROUND & AIMS: :Response rates to immune checkpoint blockade (ICB) in KRAS-mutant lung adenocarcinoma remain poor. In this issue of Cancer Discovery, Li and colleagues report an in vivo CRISPR screen of epigenetic regulators of the tumor immune microenvironment that uncovers Asf1a as a tumor-intrinsic suppressor of ICB through suppression of GM-CSF expression.See related article by Li et al., p. 270.
    背景与目标: :在KRAS突变型肺腺癌中,对免疫检查点封锁(ICB)的反应率仍然很差。在本期《癌症发现》中,Li及其同事报道了体内CRISPR筛选的肿瘤免疫微环境的表观遗传调控因子,通过抑制GM-CSF表达,发现Asf1a作为ICB的肿瘤内在抑制因子。 。,p。 270。
  • 【免疫检查站封锁反应的遗传和后生生物标志物。】 复制标题 收藏 收藏
    DOI:10.3390/jcm9010286 复制DOI
    作者列表:Xiao Q,Nobre A,Piñeiro P,Berciano-Guerrero MÁ,Alba E,Cobo M,Lauschke VM,Barragán I
    BACKGROUND & AIMS: :Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.
    背景与目标: :关卡抑制剂疗法构成了一种有前途的癌症治疗策略,其靶向免疫关卡重新激活沉默的T细胞细胞毒性。在最近的关键试验中,免疫检查点封锁(ICB)表现出持久的反应性和可接受的毒性,因此迄今为止,已有15种癌症适应症获得8种检查点抑制剂的监管批准。但是,约有85%的患者对ICB具有先天或后天抵抗力,从而限制了其临床实用性。当前反应生物标志物候选物,包括DNA突变和新抗原负荷,免疫谱以及程序性死亡配体1(PD-L1)表达,只是ICB反应的弱预测指标。因此,鉴定可以鉴定出将受益于ICB的患者的新颖,更具预测性的生物标记物是免疫疗法研究的最重要领域之一。在多种癌症中发现了异常的DNA甲基化(5mC)和羟甲基化(5hmC),并已在T细胞分化和激活过程中确定了表观基因组格局的动态变化。尽管它们在癌症免疫抑制中的作用仍有待阐明,但最近的证据表明5mC和5hmC可能是ICB敏感癌症的预后和预测生物标志物。在这篇综述中,我们描述了表观遗传现象在肿瘤免疫编辑和其他免疫逃避相关过程中的作用,提供了ICB反应生物标记物当前状态的全面更新,并突出了有前途的表观基因组生物标记物候选物。
  • 【c-Myc介导的MicroRNA-101的表观遗传沉默导致肝细胞多途径失调。】 复制标题 收藏 收藏
    DOI:10.1002/hep.26720 复制DOI
    作者列表:Wang L,Zhang X,Jia LT,Hu SJ,Zhao J,Yang JD,Wen WH,Wang Z,Wang T,Zhao J,Wang RA,Meng YL,Nie YZ,Dou KF,Chen SY,Yao LB,Fan DM,Zhang R,Yang AG
    BACKGROUND & AIMS: UNLABELLED:The MYC oncogene is overexpressed in hepatocellular carcinoma (HCC) and has been associated with widespread microRNA (miRNA) repression; however, the underlying mechanisms are largely unknown. Here, we report that the c-Myc oncogenic transcription factor physically interacts with enhancer of zeste homolog 2 (EZH2), a core enzymatic unit of polycomb repressive complex 2 (PRC2). Furthermore, miR-101, an important tumor-suppressive miRNA in human hepatocarcinomas, is epigenetically repressed by PRC2 complex in a c-Myc-mediated manner. miR-101, in turn, inhibits the expression of two subunits of PRC2 (EZH2 and EED), thus creating a double-negative feedback loop that regulates the process of hepatocarcinogenesis. Restoration of miR-101 expression suppresses multiple malignant phenotypes of HCC cells by coordinate repression of a cohort of oncogenes, including STMN1, JUNB, and CXCR7, and further increases expression of endogenous miR-101 by inhibition of PRC2 activation. In addition, co-overexpression of c-Myc and EZH2 in HCC samples was closely associated with lower expression of miR-101 (P < 0.0001) and poorer prognosis of HCC patients (P < 0.01). CONCLUSIONS:c-Myc collaborates with EZH2-containing PRC2 complex in silencing tumor-suppressive miRNAs during hepatocarcinogenesis and provides promising therapeutic candidates for human HCC.
    背景与目标: UNLABELLED:MYC癌基因在肝细胞癌(HCC)中过表达,并与广泛的microRNA(miRNA)抑制有关。但是,基本机制尚不清楚。在这里,我们报告c-Myc致癌转录因子与zeste同源物2(EZH2)(多梳抑制复合物2(PRC2)的核心酶单元)的增强子发生物理相互作用。此外,miR-101是人类肝癌中一种重要的肿瘤抑制性miRNA,它以c-Myc介导的方式被PRC2复合物表观遗传抑制。反过来,miR-101抑制PRC2的两个亚基(EZH2和EED)的表达,从而产生了一个双负反馈回路,可调节肝癌的发生过程。 miR-101表达的恢复可通过协调抑制包括STMN1,JUNB和CXCR7在内的一系列致癌基因来抑制HCC细胞的多种恶性表型,并通过抑制PRC2激活进一步增加内源性miR-101的表达。此外,HCC样本中c-Myc和EZH2的共过量表达与miR-101的较低表达(P <0.0001)和HCC患者的预后较差(P <0.01)密切相关。
    结论:c-Myc与含EZH2的PRC2复合物协同作用,在肝癌发生过程中沉默肿瘤抑制性miRNA,并为人类HCC提供了有希望的治疗候选物。
  • 【通过遗传和表观遗传机制对早期B淋巴管分化的补充调控。】 复制标题 收藏 收藏
    DOI:10.1007/s12185-013-1424-7 复制DOI
    作者列表:Yokota T,Sudo T,Ishibashi T,Doi Y,Ichii M,Orirani K,Kanakura Y
    BACKGROUND & AIMS: :Although B lymphopoiesis is one of the best-defined paradigms in cell differentiation, our knowledge of the regulatory mechanisms underlying its earliest processes, in which hematopoietic stem cells (HSCs) enter the B lineage, is limited. However, recent methodological advances in sorting progenitor cells and monitoring their epigenetic features have increased our understanding of HSC activities. It is now known that even the highly enriched HSC fraction is heterogeneous in terms of lymphopoietic potential. While surface markers and reporter proteins provide information on the sequential differentiation of B-lineage progenitors, complex interactions between transcription factors have also been shown to play a major role in this process. Epigenetic regulation of histones, nucleosomes, and chromatin appears to play a crucial background role in this elaborate transcription network. In this review, we summarize recent findings on the physiological processes of early B-lineage differentiation, which provides a new paradigm for understanding the harmonious action of genetic and epigenetic mechanisms.
    背景与目标: :尽管B淋巴细胞生成是细胞分化中定义最明确的范例之一,但我们对其最早过程(造血干细胞(HSC)进入B谱系)的调控机制的了解有限。但是,最近在分类祖细胞和监测其表观遗传学特征方面的方法学进展增加了我们对HSC活性的了解。现在已知,就淋巴生成潜力而言,即使高度富集的HSC部分也是异质的。尽管表面标志物和报告蛋白提供了有关B系祖细胞顺序分化的信息,但转录因子之间的复杂相互作用在该过程中也发挥了重要作用。组蛋白,核小体和染色质的表观遗传调控似乎在这个复杂的转录网络中起着至关重要的背景作用。在这篇综述中,我们总结了关于早期B谱系分化的生理过程的最新发现,这为理解遗传和表观遗传机制的协调作用提供了新的范例。
  • 【高和低能动精子种群的表观遗传学分析揭示了金牛座中心点周围卫星区域和功能上与精子DNA组织和维持有关的基因的甲基化变化。】 复制标题 收藏 收藏
    DOI:10.1186/s12864-019-6317-6 复制DOI
    作者列表:Capra E,Lazzari B,Turri F,Cremonesi P,Portela AMR,Ajmone-Marsan P,Stella A,Pizzi F
    BACKGROUND & AIMS: BACKGROUND:Sperm epigenetics is an emerging area of study supported by observations reporting that abnormal sperm DNA methylation patterns are associated with infertility. Here, we explore cytosine-guanine dinucleotides (CpGs) methylation in high (HM) and low motile (LM) Bos taurus sperm populations separated by Percoll gradient. HM and LM methylation patterns were investigated by bisulfite sequencing. RESULTS:Comparison between HM and LM sperm populations revealed that methylation variation affects genes involved in chromatin organization. CpG Islands (CGIs), were highly remodelled. A high proportion of CGIs was found to be methylated at low/intermediate level (20-60%) and associated to the repetitive element BTSAT4 satellite. The low/intermediate level of methylation in BTSAT4 was stably maintained in pericentric regions of chromosomes. BTSAT4 was hypomethylated in HM sperm populations. CONCLUSIONS:The characterization of the epigenome in HM and LM Bos taurus sperm populations provides a first step towards the understanding of the effect of methylation on sperm fertility. Methylation variation observed in HM and LM populations in genes associated to DNA structure remodelling as well as in a repetitive element in pericentric regions suggests that maintenance of chromosome structure through epigenetic regulation is probably crucial for correct sperm functionality.
    背景与目标: 背景:精子表观遗传学是一个新兴的研究领域,其观察结果表明,精子DNA甲基化异常与不育有关。在这里,我们探索由Percoll梯度分离的高(HM)和低运动(LM)的金牛座精子群体中的胞嘧啶-鸟嘌呤二核苷酸(CpGs)甲基化。亚硫酸氢盐测序研究了HM和LM甲基化模式。
    结果:HM和LM精子种群之间的比较表明,甲基化变异影响染色质组织所涉及的基因。 CpG岛(CGI)进行了高度重塑。发现高比例的CGI在低/中水平(20-60%)处被甲基化,并与重复元素BTSAT4卫星相关。 BTSAT4的甲基化水平处于低/中级水平,在染色体的外周中心区域保持稳定。 BTSAT4在HM精子群体中被低甲基化。
    结论:HM和LM金牛座的精子群体的表观基因组的表征为迈向了解甲基化对精子繁殖力的影响迈出了第一步。在HM和LM群体中与DNA结构重塑相关的基因以及周围中心区域的重复元件中观察到的甲基化变化表明,通过表观遗传调控维持染色体结构可能对正确的精子功能至关重要。
  • 【孟加拉国农村地区发展过程中的饥荒暴露是否与年轻成年后的代谢和表观遗传特征相关?一项历史队列研究。】 复制标题 收藏 收藏
    DOI:10.1136/bmjopen-2016-011768 复制DOI
    作者列表:Finer S,Iqbal MS,Lowe R,Ogunkolade BW,Pervin S,Mathews C,Smart M,Alam DS,Hitman GA
    BACKGROUND & AIMS: OBJECTIVES:Famine exposure in utero can 'programme' an individual towards type 2 diabetes and obesity in later life. We sought to identify, (1) whether Bangladeshis exposed to famine during developmental life are programmed towards diabetes and obesity, (2) whether this programming was specific to gestational or postnatal exposure windows and (3) whether epigenetic differences were associated with famine exposure. DESIGN:A historical cohort study was performed as part of a wider cross-sectional survey. Exposure to famine was defined through birth date and historical records and participants were selected according to: (A) exposure to famine in postnatal life, (B) exposure to famine during gestation and (C) unexposed. SETTING:Matlab, a rural area in the Chittagong division of Bangladesh. PARTICIPANTS:Young adult men and women (n=190) recruited to a historical cohort study with a randomised subsample included in an epigenetic study (n=143). OUTCOME MEASURES:Primary outcome measures of weight, body mass index and oral glucose tolerance tests (0 and 120 min glucose). Secondary outcome measures included DNA methylation using genome-wide and targeted analysis of metastable epialleles sensitive to maternal nutrition. RESULTS:More young adults exposed to famine in gestation were underweight than those postnatally exposed or unexposed. In contrast, more young adults exposed to famine postnatally were overweight compared to those gestationally exposed or unexposed. Underweight adults exposed to famine in gestation in utero were hyperglycaemic following a glucose tolerance test, and those exposed postnatally had elevated fasting glucose, compared to those unexposed. Significant differences in DNA methylation at seven metastable epialleles (VTRNA2-1, PAX8, PRDM-9, near ZFP57, near BOLA, EXD3) known to vary with gestational famine exposure were identified. CONCLUSIONS:Famine exposure in developmental life programmed Bangladeshi offspring towards diabetes and obesity in adulthood but gestational and postnatal windows of exposure had variable effects on phenotype. DNA methylation differences were replicated at previously identified metastable epialleles sensitive to periconceptual famine exposure.
    背景与目标: 目的:子宫内的饥荒暴露可以使个体“编程”走向以后的2型糖尿病和肥胖症。我们试图确定:(1)孟加拉国在发育过程中是否暴露于饥荒是否针对糖尿病和肥胖症;(2)该计划是否特定于妊娠或出生后暴露窗口;(3)表观遗传差异是否与饥荒暴露相关。
    设计:进行了一项历史队列研究,作为更广泛的横断面调查的一部分。通过出生日期和历史记录定义饥荒的暴露,并根据以下条件选择参与者:(A)出生后生活中的饥荒;(B)孕期中的饥荒暴露;(C)未暴露。
    地点:Matlab,孟加拉国吉大港地区的农村地区。
    参与者:参加历史队列研究的年轻成年男性和女性(n = 190),其表观遗传学研究(n = 143)中包含随机分组的子样本。
    观察指标:体重,体重指数和口服葡萄糖耐量试验(0和120µmin葡萄糖)的主要观察指标。次要结果测量包括使用全基因组的DNA甲基化以及对孕产妇营养敏感的亚稳态表位等位基因的靶向分析。
    结果:与出生后暴露或未暴露的婴儿相比,孕期暴露于饥荒的年轻成年人体重不足。相比之下,与未妊娠或未妊娠相比,出生后遭受饥荒的年轻人更多。体重过轻的成年人在子宫内妊娠时接受饥荒后,进行了葡萄糖耐量试验,血糖升高,与未暴露的人相比,出生后暴露的人的空腹血糖升高。确定了在七个亚稳态的等位基因(VTRNA2-1,PAX8,PRDM-9,ZFP57附近,BOLA附近,EXD3)的DNA甲基化存在显着差异,这些差异已知随妊娠饥荒的暴露而变化。
    结论:成年期孟加拉国后代在成年后患糖尿病和肥胖的过程中经历了饥荒暴露,但是妊娠和出生后的暴露时间对表型有不同的影响。 DNA甲基化差异在先前确定的对概念性饥荒暴露敏感的亚稳态表位等位基因处复制。
  • 【BARD1基因和表观遗传改变对非乳腺癌和非妇科癌症发展的影响。】 复制标题 收藏 收藏
    DOI:10.3390/genes11070829 复制DOI
    作者列表:Watters AK,Seltzer ES,MacKenzie D Jr,Young M,Muratori J,Hussein R,Sodoma AM,To J,Singh M,Zhang D
    BACKGROUND & AIMS: :Breast Cancer 1 (BRCA1) gene is a well-characterized tumor suppressor gene, mutations of which are primarily found in women with breast and ovarian cancers. BRCA1-associated RING domain 1 (BARD1) gene has also been identified as an important tumor suppressor gene in breast, ovarian, and uterine cancers. Underscoring the functional significance of the BRCA1 and BARD1 interactions, prevalent mutations in the BRCA1 gene are found in its RING domain, through which it binds the RING domain of BARD1. BARD1-BRCA1 heterodimer plays a crucial role in a variety of DNA damage response (DDR) pathways, including DNA damage checkpoint and homologous recombination (HR). However, many mutations in both BARD1 and BRCA1 also exist in other domains that significantly affect their biological functions. Intriguingly, recent genome-wide studies have identified various single nucleotide polymorphisms (SNPs), genetic alterations, and epigenetic modifications in or near the BARD1 gene that manifested profound effects on tumorigenesis in a variety of non-breast and non-gynecological cancers. In this review, we will briefly discuss the molecular functions of BARD1, including its BRCA1-dependent as well as BRCA1-independent functions. We will then focus on evaluating the common BARD1 related SNPs as well as genetic and epigenetic changes that occur in the non-BRCA1-dominant cancers, including neuroblastoma, lung, and gastrointestinal cancers. Furthermore, the pro- and anti-tumorigenic functions of different SNPs and BARD1 variants will also be discussed.
    背景与目标: :乳腺癌1(BRCA1)基因是特征明确的抑癌基因,其突变主要在患有乳腺癌和卵巢癌的女性中发现。 BRCA1相关的RING域1(BARD1)基因也已被确定为乳腺癌,卵巢癌和子宫癌的重要抑癌基因。突出BRCA1和BARD1相互作用的功能重要性,发现BRCA1基因在其RING域中普遍存在突变,通过该突变与BARD1的RING域结合。 BARD1-BRCA1异二聚体在包括DNA损伤检查点和同源重组(HR)在内的各种DNA损伤反应(DDR)途径中起着至关重要的作用。但是,BARD1和BRCA1中的许多突变也存在于其他域中,这些突变会显着影响其生物学功能。有趣的是,最近的全基因组研究已经确定了BARD1基因内或附近的各种单核苷酸多态性(SNP),遗传变异和表观遗传修饰,这些变异对各种非乳腺癌和非妇科癌症的肿瘤发生均产生了深远的影响。在这篇综述中,我们将简要讨论BARD1的分子功能,包括其依赖于BRCA1的功能以及不依赖于BRCA1的功能。然后,我们将专注于评估常见的BARD1相关SNP以及在非BRCA1占主导地位的癌症(包括神经母细胞瘤,肺癌和胃肠道癌症)中发生的遗传和表观遗传学变化。此外,还将讨论不同SNP和BARD1变体的促肿瘤和抗肿瘤功能。
  • 【金雀异黄素通过涉及活性染色质修饰的表观遗传机制在前列腺癌细胞中诱导p21WAF1 / CIP1和p16INK4a肿瘤抑制基因。】 复制标题 收藏 收藏
    DOI:10.1158/0008-5472.CAN-07-2290 复制DOI
    作者列表:Majid S,Kikuno N,Nelles J,Noonan E,Tanaka Y,Kawamoto K,Hirata H,Li LC,Zhao H,Okino ST,Place RF,Pookot D,Dahiya R
    BACKGROUND & AIMS: :Genistein (4',5,7-trihydroxyisoflavone) is the most abundant isoflavone found in the soybean. The effects of genistein on various cancer cell lines have been extensively studied but the precise molecular mechanisms are not known. We report here the epigenetic mechanism of the action of genistein on androgen-sensitive (LNCaP) and androgen-insensitive (DuPro) human prostate cancer cell lines. Genistein induced the expression of tumor suppressor genes p21 (WAF1/CIP1/KIP1) and p16 (INK4a) with a concomitant decrease in cyclins. There was a G(0)-G(1) cell cycle arrest in LNCaP cells and a G(2)-M arrest in DuPro cells after genistein treatment. Genistein also induced apoptosis in DuPro cells. DNA methylation analysis revealed the absence of p21 promoter methylation in both cell lines. The effect of genistein on chromatin remodeling has not been previously reported. We found that genistein increased acetylated histones 3, 4, and H3/K4 at the p21 and p16 transcription start sites. Furthermore, we found that genistein treatment also increased the expression of histone acetyl transferases that function in transcriptional activation. This is the first report on epigenetic regulation of various genes by genistein through chromatin remodeling in prostate cancer. Altogether, our data provide new insights into the epigenetic mechanism of the action of genistein that may contribute to the chemopreventive activity of this dietary isoflavone and have important implications for epigenetic therapy.
    背景与目标: :Genistein(4',5,7-三羟基异黄酮)是大豆中含量最高的异黄酮。金雀异黄素对各种癌细胞系的作用已被广泛研究,但确切的分子机制尚不清楚。我们在这里报告染料木黄酮对雄激素敏感(LNCaP)和雄激素不敏感(DuPro)人前列腺癌细胞系的作用的表观遗传机制。金雀异黄素诱导了抑癌基因p21(WAF1 / CIP1 / KIP1)和p16(INK4a)的表达,并伴随着细胞周期蛋白的降低。金雀异黄素处理后,LNCaP细胞中有G(0)-G(1)细胞周期停滞,而DuPro细胞中有G(2)-M停滞。金雀异黄素还诱导DuPro细胞凋亡。 DNA甲基化分析显示两种细胞系均不存在p21启动子甲基化。染料木黄酮对染色质重塑的影响以前尚未见报道。我们发现染料木黄酮增加了p21和p16转录起始位点处的乙酰化组蛋白3、4和H3 / K4。此外,我们发现金雀异黄素处理还增加了在转录激活中起作用的组蛋白乙酰基转移酶的表达。这是关于染料木黄酮通过染色质重塑在前列腺癌中对各种基因进行表观遗传调控的首次报道。总之,我们的数据为染料木黄酮作用的表观遗传机制提供了新的见解,这可能有助于这种饮食异黄酮的化学预防活性,并且对表观遗传疗法具有重要意义。
  • 【黑色素瘤和肿瘤免疫微环境的分子和表观遗传学特征与转移性患者基于伊立木单抗的免疫治疗的持久缓解有关。】 复制标题 收藏 收藏
    DOI:10.1186/s12967-016-0990-x 复制DOI
    作者列表:Seremet T,Koch A,Jansen Y,Schreuer M,Wilgenhof S,Del Marmol V,Liènard D,Thielemans K,Schats K,Kockx M,Van Criekinge W,Coulie PG,De Meyer T,van Baren N,Neyns B
    BACKGROUND & AIMS: BACKGROUND:Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. METHODS:Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). RESULTS:Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8(+) and PD-L1(+) cells than NB tumors. B cells (CD20(+)) and macrophages (CD163(+)) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. CONCLUSION:Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy.
    背景与目标: 背景:伊立木单抗(Ipi)可改善晚期黑色素瘤患者的生存率,并在10-15%的患者中增加长期获益。与此生存获益相关的肿瘤特征可能有助于优化个体化治疗策略。
    方法:从单独用Ipi(n:7)或Ipi联合树突状细胞疫苗(TriMixDC-MEL)(n:11)治疗的患者中收集新鲜冷冻的黑色素瘤转移灶。通过免疫组织化学(IHC),全转录组(RNA-seq)和甲基-DNA测序(MBD-seq)对样品进行分析。
    结果:根据临床进展将患者分为两组:持久获益(DB; 5例)和无临床获益(NB; 13例)。通过IHC分析了20个转移灶,通过RNA-和MBD-seq分析了12个转移灶。鉴定出325个基因在DB和NB之间差异表达。这些基因中的许多反映了体液和细胞的免疫反应。 MBD-seq揭示了DB和NB患者之间在与神经系统发育和神经元分化有关的基因甲基化方面的差异。与NB肿瘤相比,DB肿瘤更易被CD8()和PD-L1()细胞浸润。 B细胞(CD20())和巨噬细胞(CD163())与T细胞共定位。在几个NB样品中观察到了HLA I类和TAP-1表达的局灶性丧失。
    结论:将黑色素瘤转移与IHC,基因表达和甲基化分析相结合,可以潜在地确定基于Ipi的免疫治疗的持久应答者。
  • 【促分裂原和应激激活的蛋白激酶1调节背角神经元和伤害行为的快速表观遗传学标记。】 复制标题 收藏 收藏
    影响因子 :
    发表时间:2016-11-01
    来源期刊:Pain
    DOI:10.1097/j.pain.0000000000000679 复制DOI
    作者列表:Tochiki KK,Maiarú M,Norris C,Hunt SP,Géranton SM
    BACKGROUND & AIMS: :Phosphorylation of histone H3 at serine 10 (p-H3S10) is a marker of active gene transcription. Using cognitive models of neural plasticity, p-H3S10 was shown to be downstream of extracellular signal-regulated kinase (ERK) signalling in the hippocampus. In this study, we show that nociceptive signalling after peripheral formalin injection increased p-H3S10 expression in the ipsilateral dorsal horn. This increase was maximal 30 minutes after formalin injection and occurred mainly within p-ERK-positive neurons. Spinal p-H3S10-enhanced expression was also observed in neurokinin 1 receptor (NK1R), c-Fos, and Zif268 positive neurons and was inhibited by ablation of serotonergic descending controls. The mitogen and stress-activated protein kinase 1 (MSK1) is downstream of ERK and can induce p-H3S10. We found that, after formalin injection, most phospho-MSK1 (p-MSK1)-positive cells (87% ± 3%) expressed p-ERK and the majority of p-H3S10-positive cells (85% ± 5%) expressed p-MSK1. Inhibition of ERK activity with the MEK inhibitor SL327 reduced formalin-induced p-ERK, p-MSK1, and p-H3S10, demonstrating that spinal p-MSK1 and p-H3S10 were at least partly downstream of ERK signalling. Crucially, pharmacological blockade of spinal MSK1 activity with the novel MSK1 inhibitor SB727651A inhibited formalin-induced spinal p-H3S10 and nocifensive behaviour. These findings are the first to establish the involvement of p-H3S10 and its main kinase, MSK1, in ERK regulation of nociception. Given the general importance of ERK signalling in pain processing, our results suggest that p-H3S10 could play a role in the response to injury.
    背景与目标: :丝氨酸10(p-H3S10)处的组蛋白H3磷酸化是活性基因转录的标志。使用神经可塑性的认知模型,p-H3S10显示为海马中细胞外信号调节激酶(ERK)信号的下游。在这项研究中,我们显示注射福尔马林外围药后的伤害性信号传导会增加同侧背角中p-H3S10的表达。注射福尔马林后30分钟,这种增加最大,主要发生在p-ERK阳性神经元内。在神经激肽1受体(NK1R),c-Fos和Zif268阳性神经元中也观察到了脊髓p-H3S10增强的表达,并被消融的血清素能下降对照所抑制。有丝分裂原和应激激活蛋白激酶1(MSK1)在ERK的下游,可以诱导p-H3S10。我们发现,注射福尔马林后,大多数磷酸-MSK1(p-MSK1)阳性细胞(87%±3%)表达p-ERK,而大多数p-H3S10阳性细胞(85%±5%)表达p-ERK。 -MSK1。用MEK抑制剂SL327抑制ERK活性可降低福尔马林诱导的p-ERK,p-MSK1和p-H3S10,表明脊髓p-MSK1和p-H3S10至少部分位于ERK信号传导的下游。至关重要的是,用新型MSK1抑制剂SB727651A阻断脊柱MSK1活性的药理作用抑制了福尔马林诱导的脊柱p-H3S10和伤害行为。这些发现是第一个确定p-H3S10及其主要激酶MSK1参与ERK伤害感受调节的研究。考虑到ERK信号在疼痛处理中的重要性,我们的研究结果表明p-H3S10可能在伤害反应中发挥作用。
  • 【耐抗pralatrexate的T细胞淋巴瘤细胞系的产生揭示了表观遗传修饰剂可以克服的两种获得性耐药性模式。】 复制标题 收藏 收藏
    DOI:10.1002/gcc.22884 复制DOI
    作者列表:Scotto L,Kinahan C,Casadei B,Mangone M,Douglass E,Murty VV,Marchi E,Ma H,George C,Montanari F,Califano A,O'Connor OA
    BACKGROUND & AIMS: :While pralatrexate (PDX) has been successfully developed for the treatment of T-cell lymphoma, the mechanistic basis for its T-cell selectivity and acquired resistance remains elusive. In an effort to potentially identify synergistic combinations that might circumnavigate or delay acquired PDX resistance, we generated resistant cells lines over a broad concentration range. PDX-resistant cell lines H9-12 and H9-200 were developed, each exhibiting an IC50 of 35 and over 1000 nM, respectively. These lines were established in vitro from parental H9 cells. Expression analysis of the proteins known to be important determinants of antifolate pharmacology revealed increase expression of dihydrofolate reductase (DHFR) due to gene amplification, and reduced folate carrier1 downregulation, as the putative mechanisms of resistance in H9-12 and H9-200 cells. Cross resistance was only seen with methotrexate but not with romidepsin, azacitidine (AZA), decitabine, gemcitabine, doxorubicin, or bortezomib. Resistance to PDX was reversed by pretreatment with hypomethylating agents in a concentration-dependent fashion. Comparison of gene expression profiles of parental and resistant cell lines confirmed markedly different patterns of gene expression, and identified the dual specificity phosphatase four (DUSP4) as one of the molecular target of PDX activity. Reduced STAT5 phosphorylation following exposure to PDX was observed in the H9 but not in the H9-12 and H9-200 cells. These data suggest that combination with hypomethylating agents could be potent, and that DUSP4 and STAT5 could represent putative biomarkers of PDX activity.
    背景与目标: :尽管已成功开发出pralatrexate(PDX)用于治疗T细胞淋巴瘤,但其T细胞选择性和获得性耐药的机制基础仍然难以捉摸。为了潜在地确定可能绕过或延迟获得的PDX耐药性的协同组合,我们在较宽的浓度范围内产生了耐药细胞系。已开发出具有PDX抵抗力的细胞系H9-12和H9-200,它们的IC50分别为35和1000 overnM。这些系是从亲本H9细胞体外建立的。已知蛋白是抗叶酸药理学的重要决定因素的蛋白质的表达分析表明,由于基因扩增,二氢叶酸还原酶(DHFR)的表达增加,并且减少了叶酸携带者1的下调,这是H9-12和H9-200细胞耐药的推定机制。仅在氨甲蝶呤中观察到交叉耐药,而在罗米地辛,阿扎胞苷(AZA),地西他滨,吉西他滨,阿霉素或硼替佐米中则未见到交叉耐药。通过用次甲基化剂预处理以浓度依赖性方式逆转了对PDX的抗性。亲本和抗性细胞系基因表达谱的比较证实了基因表达的显着不同,并鉴定了双重特异性磷酸酶四(DUSP4)作为PDX活性的分子靶标之一。在H9中观察到暴露于PDX后STAT5磷酸化降低,但在H9-12和H9-200细胞中未观察到。这些数据表明,与次甲基化剂联合使用可能是有效的,而DUSP4和STAT5可能代表了PDX活性的推测生物标记。
  • 【TGF-β诱导的EMT和干性特征与肺癌的表观遗传调控有关。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-020-67325-7 复制DOI
    作者列表:Kim BN,Ahn DH,Kang N,Yeo CD,Kim YK,Lee KY,Kim TJ,Lee SH,Park MS,Yim HW,Park JY,Park CK,Kim SJ
    BACKGROUND & AIMS: :Transforming growth factor-β (TGF-β) promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT). EMT is often related with acquisition of stemness characteristics. The objective of this study was to determine whether EMT and stemness characteristics induced by TGF-β might be associated with epigenetic regulation in lung cancer. A human normal lung epithelial cell line and four lung cancer cell lines were treated with TGF-β. Transcriptome analysis of BEAS-2B and A549 cells incubated with TGF-β were analyzed through next-generation sequencing (NGS). Western blotting was carried out to investigate expression levels of epithelial and mesenchymal markers. Wound healing and Matrigel invasion assay, sphere formation assay, and in vivo mice tumor model were performed to evaluate functional characteristics of EMT and stemness acquisition. To investigate whether activation of EMT and stem cell markers might be involved in epigenetic regulation of lung cancer, experiment using a DNA methyltransferase inhibitor (5-azacytidine, AZA), methylation-specific PCR (MSP) and bisulfite sequencing were performed. NGS revealed changes in expression levels of EMT markers (E-cadherin, N-cadherin, fibronectin, vimentin, slug and snail) and stem cell markers (CD44 and CD87) in both BEAS-2B and A549 cells. Functional analysis revealed increased migration, invasion, sphere formation, and tumor development in mice after TGF-β treatment. Expression of slug and CD87 genes was activated following treatment with AZA and TGF-β. MSP and bisulfite sequencing indicated DNA demethylation of slug and CD87 genes. These results suggest that TGF-β induced EMT and cancer stemness acquisition could be associated with activation of slug and CD87 gene by their promoter demethylation.
    背景与目标: :转化生长因子-β(TGF-β)通过诱导上皮-间质转化(EMT)促进肿瘤侵袭和转移。 EMT通常与词干特征的获取有关。这项研究的目的是确定TGF-β诱导的EMT和干性特征是否可能与肺癌的表观遗传调控有关。用TGF-β处理人正常肺上皮细胞系和四种肺癌细胞系。通过下一代测序(NGS)分析了用TGF-β孵育的BEAS-2B和A549细胞的转录组分析。进行了蛋白质印迹以研究上皮和间充质标志物的表达水平。进行伤口愈合和基质胶侵袭测定,球形成测定和体内小鼠肿瘤模型以评估EMT和干性获得的功能特征。为了研究EMT和干细胞标志物的激活是否可能参与肺癌的表观遗传调控,使用DNA甲基转移酶抑制剂(5-氮杂胞苷,AZA),甲基化特异性PCR(MSP)和亚硫酸氢盐测序进行了实验。 NGS揭示了BEAS-2B和A549细胞中EMT标记(E-钙黏着蛋白,N-钙黏着蛋白,纤连蛋白,波形蛋白、,和蜗牛)和干细胞标记(CD44和CD87)表达水平的变化。功能分析显示,在TGF-β处理后,小鼠的迁移,侵袭,球形成和肿瘤发展增加。用AZA和TGF-β处理后,Slug和CD87基因的表达被激活。 MSP和亚硫酸氢盐测序表明,Slug和CD87基因的DNA脱甲基。这些结果表明,TGF-β诱导的EMT和癌症干性获得可能与它们的启动子去甲基化与Slug和CD87基因的激活有关。
  • 【表观遗传学药物库的筛选确定了4-(((羟基氨基)羰基)-N-(2-羟乙基)-N-苯基-苯乙酰胺,其通过独立于表观遗传机制抑制酪氨酸酶活性而降低了黑色素的合成。】 复制标题 收藏 收藏
    DOI:10.3390/ijms21134589 复制DOI
    作者列表:Song H,Hwang YJ,Ha JW,Boo YC
    BACKGROUND & AIMS: :The aim of this study was to identify novel antimelanogenic drugs from an epigenetic screening library containing various modulators targeting DNA methyltransferases, histone deacetylases, and other related enzymes/proteins. Of 141 drugs tested, K8 (4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-phenyl-benzeneacetamide; HPOB) was found to effectively inhibit the α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis in B16-F10 murine melanoma cells without accompanying cytotoxicity. Additional experiments showed that K8 did not significantly reduce the mRNA and protein level of tyrosinase (TYR) or microphthalmia-associated transcription factor (MITF) in cells, but it potently inhibited the catalytic activity TYR in vitro (IC50, 1.1-1.5 µM) as compared to β-arbutin (IC50, 500-700 µM) or kojic acid (IC50, 63 µM). K8 showed copper chelating activity similar to kojic acid. Therefore, these data suggest that K8 inhibits cellular melanin synthesis not by downregulation of TYR protein expression through an epigenetic mechanism, but by direct inhibition of TYR catalytic activity through copper chelation. Metal chelating activity of K8 is not surprising because it is known to inhibit histone deacetylase (HDAC) 6 through zinc chelation. This study identified K8 as a potent inhibitor of cellular melanin synthesis, which may be useful for the treatment of hyperpigmentation disorders.
    背景与目标: :这项研究的目的是从表观遗传学筛选文库中鉴定出新型的产炭黑药物,其中包含针对DNA甲基转移酶,组蛋白脱乙酰基酶和其他相关酶/蛋白质的各种调节剂。在测试的141种药物中,发现K8(4-(((羟基氨基)羰基)-N-(2-羟乙基)-N-苯基苯乙酰胺; HPOB)有效抑制α-黑素细胞刺激激素(α-MSH)-诱导B16-F10鼠黑色素瘤细胞中黑色素的合成而没有细胞毒性。其他实验表明,K8不会显着降低细胞中酪氨酸酶(TYR)或小眼症相关转录因子(MITF)的mRNA和蛋白水平,但它可以有效抑制TYR的体外催化活性(IC50,1.1-1.5 µM)。与β-熊果苷(IC50,500-700 µM)或曲酸(IC50,63 µM)相比。 K8表现出与曲酸相似的铜螯合活性。因此,这些数据表明,K8不是通过表观遗传机制抑制TYR蛋白表达,而是通过铜螯合直接抑制TYR催化活性来抑制细胞黑色素合成。 K8的金属螯合活性不足为奇,因为已知它可以通过锌螯合抑制组蛋白脱乙酰基酶(HDAC)6。这项研究确定K8是细胞黑色素合成的有效抑制剂,可能对治疗色素沉着过度有用。

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