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Epigenetic modulation by green tea in prevention of photocarcinogenesis

绿茶的表观遗传调节预防光致癌

基本信息

批准号：
8033727
负责人：
SANTOSH KUMAR KATIYAR
金额：
$ 15.45万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8033727
关键词：
Accounting Acetylation Address Adverse effects Affect Beverages CDKN2A gene Carcinogenesis Mechanism Caucasians Caucasoid Race Chemopreventive Agent Chronic Consumption Cutaneous Cutaneous Melanoma DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Sequence Data Defect Development Elements Enzymes Epigallocatechin Gallate Epigenetic Process Event Exposure to Future Gene Expression Regulation Genes Genetic Genome Stability Goals Green tea Histone Acetylation Histone Deacetylation Histones Human Hypermethylation In Vitro Inbred HRS Mice Incidence Inherited Kinetics Knowledge Lead Malignant Neoplasms Mediating Methylation Modification Molecular Mus Oncogenes Organ Pathway interactions Pharmaceutical Preparations Phytochemical Pilot Projects Play Prevention Preventive Process Public Health Research Design Risk Role Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Squamous cell carcinoma Testing Time Transferase Tumor Suppressor Genes Tumor Suppressor Proteins UV Radiation Exposure UV induced UVB induced Ultraviolet B Radiation Ultraviolet Rays United States Up-Regulation base cancer initiation carcinogenesis dietary supplements drinking water histone modification innovation interest keratinocyte mouse model novel strategies prevent public health relevance response skin cancer prevention tumor tumor progression tumorigenesis ultraviolet

项目摘要

DESCRIPTION (provided by applicant): Overexposure of the human skin to solar ultraviolet (UV) radiation is the major etiologic factor for the development of melanoma and non-melanoma skin cancers in the United States, with the non-melanoma skin cancer being the most common cutaneous malignancy. Although epigenetic mechanisms have been implicated in UVB-induced skin carcinogenesis, the mechanisms have not been fully characterized. Importantly, epigenetic mechanisms are potentially reversible and represent attractive targets for the prevention of the development of UVB-induced cutaneous malignancies. We have now generated preliminary data that indicate that chronic exposure of the mouse skin to UV radiation induces epigenetic alterations which include: DNA hypermethylation, increases in DNA methyltransferase (Dnmt) activity, and increases in histone de-acetylation and that these alterations may lead to the silencing of tumor suppressor genes in mouse skin. Furthermore, we have made the unique observation that a non-toxic phytochemical may act to prevent photocarcinogenesis through inhibition of epigenetic mechanisms. We had demonstrated previously that administration of green tea polyphenols (GTPs, 0.2%, w/v) in drinking water of mice significantly inhibits UV- induced skin tumor development in terms of tumor incidence (% mice with tumors) and tumor multiplicity. We have now generated preliminary data that suggest that administration of GTPs in drinking water of mice inhibits UVB-induced DNA hypermethylation and Dnmt activity in the skin. Based on our preliminary data, we have formulated the innovative hypothesis that exposure of the skin to UV radiation results in the DNA hypermethylation which leads to epigenetic silencing of key tumor suppressor genes during photocarcinogenesis. We also hypothesize that GTPs prevent UV-induced skin tumor development, at least in part, through the prevention of epigenetic alterations associated with UV radiation. Our long- term goal is to fully test this hypothesis. The objectives of this exploratory R21 application are to verify and extend our preliminary results using the SKH-1 hairless mouse model in order to generate the data necessary for the design of studies that will rigorously test the central hypothesis in mouse and human skin and establish the molecular basis for the observed data. Thus, we propose two complementary Specific Aims: (1) To determine whether inhibition of photocarcinogenesis by GTPs is mediated through inhibition of UVB-induced DNA hypermethylation and Dnmt activity in UVB-exposed skin and tumors, and (2) To determine the molecular mechanisms by which GTPs control epigenetic modulators which regulate key tumor suppressors during photocarcinogenesis. In vitro analyses using human keratinocytes and epigenetic modulating drugs will be used to verify the data generated using the mouse model. The results obtained from this study will generate new knowledge concerning the identity of the epigenetic mechanisms involved in photocarcinogenesis and should indicate whether GTPs exert their skin cancer chemopreventive effects by inhibiting these responses. We address a major public health concern as overexposure of the human skin to solar UV radiation is the major etiologic factor for the development of melanoma and non-melanoma skin cancers in the United States. The proposed studies will provide critical new data concerning UVB-induced carcinogenesis and will identify mechanisms by which green tea may act to prevent/correct UV-induced deficiencies. The development of new strategies using green tea polyphenols as a dietary supplement may help to reduce the risk of skin cancer in humans. There is world-wide interest in green tea as a cancer chemopreventive agent for humans as it is a non-toxic, affordable, popular beverage and is effective in a wide range of organs. PUBLIC HEALTH RELEVANCE: Chronic exposure of the skin to solar ultraviolet (UV) radiation induces multiple adverse effects including the risk of skin cancer development. The epigenetic modifications that occur in DNA play a significant role in the regulation of gene expression and lead to the development of cancers. In the current application, we will determine the molecular mechanism of epigenetic changes which leads to epigenetic silencing of key tumor suppressor genes during photocarcinogenesis. We will also determine whether administration of green tea polyphenols in drinking water of mice prevents photocarcinogenesis in mice through the inhibition of UVB- induced epigenetic alterations and silencing of tumor suppressor genes.

描述(由申请人提供)：人体皮肤过度暴露于太阳紫外线(UV)辐射是美国黑色素瘤和非黑色素瘤皮肤癌发展的主要病因，其中非黑色素瘤皮肤癌是最常见的皮肤恶性肿瘤。虽然表观遗传机制已被认为与UVB诱导的皮肤癌有关，但其机制尚未完全确定。重要的是，表观遗传机制可能是可逆的，并且是预防UVB诱导的皮肤恶性肿瘤发展的有吸引力的靶点。我们现在已经产生了初步的数据表明，长期暴露在紫外线辐射下的小鼠皮肤会诱导表观遗传学改变，包括：DNA超甲基化，DNA甲基转移酶(DNMT)活性增加，组蛋白去乙酰化增加，这些改变可能导致小鼠皮肤中肿瘤抑制基因的沉默。此外，我们还观察到一种无毒的植物化学物质可能通过抑制表观遗传机制来预防光癌的发生。我们以前已经证明，在小鼠饮用水中加入绿茶多酚(GTPs，0.2%，w/v)可以显著抑制紫外线诱导的皮肤肿瘤的发生(肿瘤发生率(带瘤鼠的百分比)和肿瘤的多样性)。我们现在已经产生了初步数据，表明在小鼠饮用水中给予GTPS可以抑制UVB诱导的皮肤DNA超甲基化和DNMT活性。基于我们的初步数据，我们提出了一个创新的假设，即皮肤暴露在紫外线辐射下会导致DNA超甲基化，从而导致光致癌过程中关键的肿瘤抑制基因的表观遗传沉默。我们还假设，GTP至少部分地通过防止与紫外线辐射相关的表观遗传学改变来防止紫外线诱导的皮肤肿瘤的发展。我们的长期目标是充分检验这一假设。这一探索性的R21应用程序的目标是使用SKH-1无毛小鼠模型验证和扩展我们的初步结果，以便生成设计研究所需的数据，这些研究将在小鼠和人类皮肤上严格测试中心假设，并为观察到的数据建立分子基础。因此，我们提出了两个互补的特异性目标：(1)确定GTPS对光癌的抑制是否通过抑制UVB诱导的皮肤和肿瘤中的DNA高甲基化和DNMT活性来实现；(2)确定GTPS控制表观遗传调节因子的分子机制，表观遗传调节因子在光致癌过程中调节关键的肿瘤抑制因子。使用人类角质形成细胞和表观遗传调节药物进行的体外分析将用于验证使用小鼠模型产生的数据。这项研究的结果将产生关于光致癌的表观遗传机制的识别的新知识，并应该表明GTP是否通过抑制这些反应来发挥其皮肤癌化学预防作用。我们解决了一个主要的公共卫生问题，因为人类皮肤过度暴露于太阳紫外线辐射是美国黑色素瘤和非黑色素瘤皮肤癌发展的主要病因因素。这项拟议的研究将提供有关UVB诱导致癌的关键新数据，并将确定绿茶预防/纠正UV诱导的缺陷的机制。利用绿茶多酚作为膳食补充剂的新策略的开发可能有助于降低人类患皮肤癌的风险。绿茶是一种无毒、价格实惠、受欢迎的饮料，而且对多种器官有效，因此作为人类癌症化学防御剂的研究受到了全世界的广泛关注。与公共健康相关：皮肤长期暴露在太阳紫外线(UV)辐射下会导致多种不良影响，包括皮肤癌的风险。DNA中发生的表观遗传修饰在基因表达调控中发挥着重要作用，并导致癌症的发展。在目前的应用中，我们将确定表观遗传变化导致关键抑癌基因在光癌发生过程中表观遗传沉默的分子机制。我们还将确定在小鼠饮用水中加入绿茶多酚是否通过抑制UVB诱导的表观遗传改变和肿瘤抑制基因的沉默来防止小鼠的光癌发生。