Dietary HDAC Inhibitors in Colon Cancer Prevention
膳食 HDAC 抑制剂预防结肠癌
基本信息
- 批准号:7456211
- 负责人:
- 金额:$ 30.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2013-01-31
- 项目状态:已结题
- 来源:
- 关键词:1,1-Dimethylhydrazine1,2-DimethylhydrazineAdoptedAffectAntioxidantsApoptosisBinding SitesBiological MarkersBroccoli - dietaryCDKN1A geneCell CycleChemopreventive AgentChemoprotectionChemoprotective AgentClinical TrialsColon CarcinomaColonic NeoplasmsColonoscopyConditionDNADNA SequenceDailyDevelopmentDietDimethylhydrazinesEpigenetic ProcessEventFoodGarlicGene ExpressionGene SilencingGenesGrowthHT29 CellsHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorHistone deacetylase inhibitionHistonesHumanHuman VolunteersImmunoblottingIn VitroIndividualIngestionIntakeInterventionMalignant NeoplasmsMusMutationNormal CellOrganParentsPathway interactionsPatientsPatternPeripheral Blood Mononuclear CellPre-Clinical ModelPromoter RegionsProteinsPublic HealthReportingRepressionResponse ElementsRoleSignal TransductionSiteSmall Interfering RNASp1 Transcription FactorSp3 Transcription FactorStagingSulforaphaneTestingTherapeuticTherapeutic AgentsTranslatingTumor SuppressionTumor Suppressor GenesUnited States National Institutes of HealthWorkallyl sulfidecancer cellcancer preventioncell suicidecolorectal cancer screeninghuman subjectin vivoinhibitor/antagonistinnovationinterestnoveloncoprotein p21promoterresearch studyresponsetranslational study
项目摘要
DESCRIPTION (provided by applicant):
This application responds to PA-06-412 "Diet, epigenetic events & cancer prevention" by focusing on food components that act as histone deacetylase (HDAC) inhibitors. HDAC inhibitors are receiving increasing interest as cancer therapeutic agents, with the realization that histone acetylation is altered in many cancers. Potent HDAC inhibitors `de- repress' epigenetically silenced genes, such as P21/WAF1, through Sp1/Sp3 transcription factor binding sites in the corresponding gene promoters, causing growth arrest/apoptosis in cancer cells. The PI has proposed that dietary HDAC inhibitors might act similarly in the therapeutic setting, but because of their regular ingestion in foods they also serve a chemopreventive role via epigenetic `priming' of gene expression in normal cells. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) from broccoli and organosulfur compounds from garlic are effective chemopreventive agents because the parent compound(s) activate Nrf2/ARE signaling whereas the metabolites inhibit HDAC activity, thereby de-repressing genes such as P21 that regulate the cell cycle and apoptosis. By acting through Sp1/Sp3 sites in gene promoters, HDAC inhibitory effects of dietary agents can occur independently of the Nrf2/ARE pathway. Aims 1-3 are sequential, starting with individual dietary compounds and HDAC inhibitor mechanisms in human colon cancer cells (Aim 1), followed by colon tumor suppression studies in vivo (Aim 2), and combined agents in vivo (Aim 3A,B), ending with translational studies in humans (Aim 3C). Aim 1. In human colon cancer cells, define the specific HDACs that associate with the promoter region of the P21 gene, and the changes in these HDACs following treatment with dietary HDAC inhibitors. Using immunoblotting, ChIP/re-ChIP, qRT-PCR and siRNA knockdown, systematically examine HDACs associated with the promoter region of P21, their de-recruitment in response to dietary HDAC inhibitors, and the role of specific transcription factors (Sp1, Sp3) in de-repressing p21, in HT29 cells treated with SFN (Aim 1A) or garlic compounds (Aim 1B). Aim 2. Test the hypothesis that, post-initiation, dietary HDAC inhibitors increase histone acetylation and de- repress p21, thereby suppressing colon tumor formation in 1,2-dimethylhydrazine (DMH)-treated mice. Show that tumor suppression is correlated with HDAC inhibition, induction of acetylated histones, and de-repression of p21 in mice given SFN (Aim 2A) or garlic organosulfur compounds (Aim 2B). Aim 3. Examine the cooperative effects of SFN and garlic compounds as dietary HDAC inhibitors in mice, and translate the findings into human volunteers, using a `whole food' approach that combines SFN-rich broccoli sprouts and garlic oil supplements. Show that SFN and garlic compounds cooperate to suppress DMH- induced colon tumors in mice (Aim 3A), and cause HDAC inhibition and histone hyperacetylation in normal cells of the mouse (Aim 3B), i.e. in peripheral blood mononuclear cells (PBMCs). Test the hypothesis that, in human volunteers, broccoli sprouts and garlic oil supplements cause HDAC inhibition and histone hyperacetylation in PBMCs (Aim 3C). Unlike genetic changes associated with cancer, epigenetic changes are potentially modifiable; thus, HDAC inhibitory effects of dietary agents are worthy of study, with implications for cancer prevention and treatment. PUBLIC HEALTH RELEVANCE: Cancer development is often considered in terms of genetic alterations in the DNA sequence (i.e. mutations), but recent work has implicated so-called `epigenetic' changes. The latter involve reversible alterations in the proteins that associate with DNA, and affect how genes are turned `on' or `off'. This project examines how chemoprotective factors in broccoli and garlic, working through epigenetic mechanisms, can turn on tumor suppressor genes, thereby causing colon cancer cells to halt their growth and/or rapidly undergo cell suicide.
描述(由申请人提供):
本申请响应PA-06-412“饮食,表观遗传事件和癌症预防”,重点关注作为组蛋白脱乙酰酶(HDAC)抑制剂的食物成分。随着认识到组蛋白乙酰化在许多癌症中被改变,HDAC抑制剂作为癌症治疗剂受到越来越多的关注。有效的HDAC抑制剂通过相应基因启动子中的Sp1/Sp3转录因子结合位点“去抑制”表观遗传学沉默的基因,如P21/WAF 1,导致癌细胞的生长停滞/凋亡。PI提出,饮食HDAC抑制剂在治疗环境中可能起类似作用,但由于它们在食物中的常规摄入,它们也通过正常细胞中基因表达的表观遗传“引发”起化学预防作用。中心假设是来自西兰花的萝卜硫素(SFN)和来自大蒜的有机硫化合物是有效的化学预防剂,因为母体化合物激活Nrf 2/ARE信号传导,而代谢物抑制HDAC活性,从而去抑制调节细胞周期和凋亡的基因,如P21。通过基因启动子中的Sp1/Sp3位点起作用,膳食剂的HDAC抑制作用可以独立于Nrf 2/ARE途径发生。目的1-3是连续的,从人结肠癌细胞中的单个膳食化合物和HDAC抑制剂机制开始(目的1),随后是体内结肠肿瘤抑制研究(目的2),以及体内组合药剂(目的3A、B),以人体中的转化研究结束(目的3C)。目标1.在人结肠癌细胞中,定义与P21基因启动子区相关的特定HDAC,以及用饮食HDAC抑制剂治疗后这些HDAC的变化。使用免疫印迹、ChIP/re-ChIP、qRT-PCR和siRNA敲除,系统地检查与P21启动子区域相关的HDAC、其响应于饮食HDAC抑制剂的去募集以及特异性转录因子(Sp1、Sp3)在用SFN(Aim 1A)或大蒜化合物(Aim 1B)处理的HT 29细胞中去抑制p21中的作用。目标二。测试以下假设:在开始后,饮食HDAC抑制剂增加组蛋白乙酰化并去抑制p21,从而抑制1,2-二甲基肼(DMH)处理的小鼠中的结肠肿瘤形成。显示肿瘤抑制与HDAC抑制、乙酰化组蛋白的诱导以及给予SFN(Aim 2A)或大蒜有机硫化合物(Aim 2B)的小鼠中p21的去抑制相关。目标3。研究SFN和大蒜化合物作为小鼠饮食HDAC抑制剂的协同作用,并将研究结果转化为人类志愿者,使用一种“全食物”方法,将富含SFN的西兰花芽和大蒜油补充剂结合起来。显示SFN和大蒜化合物协同抑制小鼠中DMH诱导的结肠肿瘤(Aim 3A),并在小鼠的正常细胞(即外周血单核细胞(PBMC))中引起HDAC抑制和组蛋白超乙酰化(Aim 3B)。在人类志愿者中,测试西兰花芽和大蒜油补充剂导致PBMC中HDAC抑制和组蛋白过度乙酰化的假设(Aim 3C)。与癌症相关的遗传变化不同,表观遗传变化是潜在的可修改的;因此,饮食制剂的HDAC抑制作用值得研究,对癌症预防和治疗有意义。公共卫生相关性:癌症的发展通常被认为是DNA序列的遗传改变(即突变),但最近的工作涉及所谓的“表观遗传”变化。后者涉及与DNA相关的蛋白质的可逆性改变,并影响基因的“打开”或“关闭”。该项目研究了西兰花和大蒜中的化学保护因子如何通过表观遗传机制发挥作用,可以打开肿瘤抑制基因,从而导致结肠癌细胞停止生长和/或迅速进行细胞自杀。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Roderick H Dashwood其他文献
Roderick H Dashwood的其他文献
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