Folate and PSMA Interact to Regulate DNA Methylation and Prostate Carcinogenesis

叶酸和 PSMA 相互作用调节 DNA 甲基化和前列腺癌发生

基本信息

批准号：
8610804
负责人：
Dean John Bacich
金额：
$ 4.37万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2010-04-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610804
关键词：
Adult Affect Affinity Age Age-Months Alleles American American Cancer Society Amino Acids Animals BMI1 gene Binding Biological Assay Boxing Breast Carbon Cell Proliferation Cells Cereals Cessation of life Chromatin Clinical Colorectal DNA DNA Methylation DNMT3a Data Defect Development Diet Disease Disease Outcome EZH2 gene Endothelial Cells Environment Epigenetic Process Epithelial Cells Estradiol Event Exposure to Fibrous capsule of kidney Folate Folic Acid Food Gene Expression Genes Genitourinary system Genome Genomic DNA Genomic Instability Genomics Glutamate Carboxypeptidase II Growth High Prevalence Histones Human Hydrolase Hypermethylation Implant In Vitro Intake Intervention Intestines Knock-out LNCaP Lead Leucovorin Malignant Neoplasms Malignant neoplasm of prostate Mass Spectrum Analysis Measures Mediating Membrane Mesenchyme Methionine Methylation Modeling Mus National Health and Nutrition Examination Survey Nature Nutritional Nutritional Study Outcome PC3 cell line Pattern Play Population Pregnancy Prostate Prostatic Prostatic Neoplasms Proteins Proto-Oncogene Proteins c-akt Publishing Recombinants Regulation Relative (related person)Reporting Retroelements Risk Role Safety Serum Folate Level Small Interfering RNA Subfamily lentivirinae Supplementation Techniques Testing Testosterone Time Tissues Transgenic Mice Transgenic Organisms Tumor Suppressor Genes Twin Studies Up-Regulation Virus age group aged angiogenesis base cancer initiation capsule carcinogenesis cellular transduction demethylation dietary supplements epigenomics extracellular feeding fortification human glutamate carboxypeptidase II in vitro Model in vivo in vivo Model inhibitor/antagonist knock-down male matrigel men methyl group mouse model neovasculature novel older men polyglutamates pre-clinical prevent programs promoter prostate cancer cell prostate carcinogenesis protective effect public health relevance research study response tumor tumor growth tumor initiation tumor progression tumorigenesis tumorigenic uptake vector

项目摘要

DESCRIPTION (provided by applicant): Folate, as part of the one carbon cycle, is critical for the de novo synthesis of S-adenosyl methionine (SAM). SAM, in turn, provides the methyl group for DNA methylation, a key mode of epigenetic regulation. Studies have shown that manipulation of folate levels during gestation alters the epigenetic status of genes, and that treatment with methyl donors in adulthood reverses DNA methylation changes. Given the effect of folate levels on DNA methylation, it is not surprising that dietary folate status influences the risk for several cancers. Folate is also essential for cell proliferation. Accordingly, animal studies show that the timing of folate intake modulates disease outcome: supplementation protects against tumor initiation while folate depletion inhibits tumor growth. The prostate has a high requirement for folate, and also seems susceptible to alterations in DNA methylation, suggesting that folate might also play a role in prostate cancer. We have developed an in vitro model, in which we can produce simultaneous tumor suppressor gene promoter hypermethylation in an overall context of global hypomethylation reminiscent of prostate cancer, by manipulating folic acid levels. In addition, we have shown that a protein intimately related to intracellular folate levels, Prostate-Specific Membrane Antigen (PSMA), contributes to prostate carcinogenesis. PSMA, a unique folate hydrolase, and possible folate transporter, undergoes significant up-regulation in prostate cancer and in the endothelial cells of tumor neovasculature. Moreover, in the presence of low levels of folate, PSMA expression increases cell invasiveness, an activity important for both tumor formation and progression. Our hypothesis is: Low, followed by excess levels of available folates in the prostate over an extended period of time leads to carcinogenesis. To test this hypothesis we will use the following specific aims; 1) Determine if (a) PSMA expression regulates intracellular folate levels, and (b) if folate levels regulate DNA methylation in prostate tissues in a novel in vivo model, 2) Ascertain if low levels of folates increase the invasive capacity of PSMA, and lead to genomic hypomethylation, DNA instability and subsequently carcinogenesis and 3) Establish if, prior to initiation of prostate carcinogenesis folate supplementation is protective, and if, following initiation, folate supplementation promotes prostate tumor growth and progression by enhanced uptake of systemic folate in the prostate mediated by PSMA, and by altering epigenetic programming. Relevance: Recent reports describe a significant association between folate supplementation and prostate cancer. Folic acid fortification of the U.S.diet in 1998 has converted the population from a largely folate-deficient to folate-replete. Studies have shown that excess folic acid intake increases the risk of breast, colorectal, and now, prostate cancer. We have shown that nearly 2 million men aged 60 or above have serum folate levels greater than 5 fold adequate. This fact, in combination with the high prevalence of preclinical prostate cancer in men of the >60 age group, underscores the importance of investigating the relationship between folate and prostate cancer.

描述（由申请人提供）：叶酸作为单碳循环的一部分，对于 S-腺苷甲硫氨酸 (SAM) 的从头合成至关重要。 SAM 反过来为 DNA 甲基化提供甲基，这是表观遗传调控的关键模式。研究表明，妊娠期间叶酸水平的控制会改变基因的表观遗传状态，而成年期甲基供体的治疗可以逆转 DNA 甲基化的变化。鉴于叶酸水平对 DNA 甲基化的影响，膳食叶酸状态影响多种癌症的风险也就不足为奇了。叶酸对于细胞增殖也至关重要。因此，动物研究表明，叶酸摄入时间可调节疾病结果：补充叶酸可防止肿瘤发生，而叶酸消耗则可抑制肿瘤生长。前列腺对叶酸的需求量很高，并且似乎也容易受到 DNA 甲基化改变的影响，这表明叶酸也可能在前列腺癌中发挥作用。我们开发了一种体外模型，在该模型中，我们可以通过操纵叶酸水平，在整体低甲基化（让人想起前列腺癌）的整体背景下同时产生肿瘤抑制基因启动子高甲基化。此外，我们还发现一种与细胞内叶酸水平密切相关的蛋白质——前列腺特异性膜抗原（PSMA），有助于前列腺癌的发生。 PSMA 是一种独特的叶酸水解酶，也是可能的叶酸转运蛋白，在前列腺癌和肿瘤新血管系统的内皮细胞中显着上调。此外，在叶酸水平较低的情况下，PSMA 表达会增加细胞侵袭性，这对肿瘤形成和进展都很重要。我们的假设是：前列腺中可用叶酸水平较低，并且在较长时间内过量会导致癌变。为了检验这一假设，我们将使用以下具体目标； 1) 确定 (a) PSMA 表达是否调节细胞内叶酸水平，以及 (b) 在新型体内模型中叶酸水平是否调节前列腺组织中的 DNA 甲基化，2) 确定低水平的叶酸是否会增加 PSMA 的侵袭能力，以及导致基因组低甲基化、DNA 不稳定以及随后的致癌作用，以及 3) 确定在前列腺癌发生之前补充叶酸是否具有保护作用，以及在开始后叶酸补充是否会促进前列腺肿瘤生长通过 PSMA 介导的前列腺中全身叶酸的增强摄取以及通过改变表观遗传编程来实现进展。相关性：最近的报告描述了叶酸补充与前列腺癌之间的显着关联。 1998 年，美国饮食中的叶酸强化已将人们从叶酸严重缺乏转变为叶酸充足。研究表明，摄入过多的叶酸会增加患乳腺癌、结直肠癌以及现在的前列腺癌的风险。我们已经证明，近 200 万 60 岁或以上的男性的血清叶酸水平超过充足水平的 5 倍。这一事实，再加上 60 岁以上年龄组男性临床前前列腺癌的高患病率，强调了研究叶酸与前列腺癌之间关系的重要性。