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：
8444524
负责人：
Dean John Bacich
金额：
$ 28.71万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444524
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 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）：作为一个碳循环的一部分，叶酸对于S-腺苷蛋氨酸（SAM）的从头合成至关重要。反过来，SAM为DNA甲基化提供了甲基化，这是表观遗传调节的关键模式。研究表明，妊娠期间对叶酸水平的操纵改变了基因的表观遗传状态，并且在成年期间用甲基供体的治疗逆转了DNA甲基化的变化。鉴于叶酸水平对DNA甲基化的影响，饮食叶酸状况会影响多种癌症的风险毫不奇怪。叶酸对于细胞增殖也是必不可少的。因此，动物研究表明，叶酸摄入的时机调节疾病的结果：补充可防止肿瘤起始，而叶酸耗竭会抑制肿瘤的生长。前列腺对叶酸有很高的要求，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来产生同时的肿瘤抑制基因启动子高甲基化的高甲基化。此外，我们已经表明，与细胞内叶酸水平，前列腺特异性膜抗原（PSMA）密切相关的蛋白质有助于前列腺致癌。 PSMA是一种独特的叶酸水解酶和可能的叶酸转运蛋白，在前列腺癌和肿瘤新生血管内的内皮细胞中经历了明显的上调。此外，在叶酸水平较低的情况下，PSMA表达会增加细胞侵袭性，这对于肿瘤形成和进展都很重要。我们的假设是：低，其次是在长时间的前列腺中过量的叶酸水平过多会导致致癌作用。为了检验这一假设，我们将使用以下特定目标； 1）确定（a）PSMA表达是否调节细胞内叶酸水平，以及（b）如果叶酸水平在新型的体内模型中调节前列腺组织中的DNA甲基化，2）确定较低的叶状水平是否会增加PSMA的侵入性能力，并导致基因组高甲基的不稳定性和后续碳纤维的carcINESELISION和3）的启动，以建立IF的carcINESIDINGINES IF，在IF的启动中，IF启动IF，IF in IF，IF IF，IF IF）IF，IF IF启动IF，以IF的启动，以IF的启动，以IF的启动，以IF的IF启动，以实现IF的IF摄入。补充是保护性的，并且如果启动后，叶酸补充剂会通过增强PSMA介导的前列腺中的全身性叶酸的吸收，并通过改变表观遗传学编程来促进前列腺肿瘤的生长和进展。相关性：最近的报告描述了叶酸补充剂与前列腺癌之间的显着关联。 1998年，美国叶酸的叶酸强化已将人口从很大的叶酸转化为叶酸的重复。研究表明，过量的叶酸摄入会增加乳腺癌，结直肠癌和现在的前列腺癌的风险。我们已经表明，近200万名60岁或更高的男性的血清叶酸水平大于5倍。这一事实结合了> 60岁年龄段的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。