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

• 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
• 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

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.

性状（由申请人提供）：叶酸作为一碳循环的一部分，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，在妊娠期间操纵叶酸水平会改变基因的表观遗传状态，并且在成年期用甲基供体治疗会逆转DNA甲基化变化。考虑到叶酸水平对DNA甲基化的影响，饮食中的叶酸水平影响几种癌症的风险就不足为奇了。叶酸对细胞增殖也是必不可少的。因此，动物研究表明，叶酸摄入的时间调节疾病的结果：补充叶酸可防止肿瘤的发生，而叶酸消耗可抑制肿瘤的生长。前列腺对叶酸的需求很高，而且似乎也容易受到DNA甲基化改变的影响，这表明叶酸可能在前列腺癌中也起作用。我们已经开发了一种体外模型，在这种模型中，我们可以通过操纵叶酸水平，在整体甲基化水平低下的背景下同时产生肿瘤抑制基因启动子高甲基化，这让人联想到前列腺癌。此外，我们已经表明，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，也可能是叶酸转运蛋白，在前列腺癌和肿瘤新生血管的内皮细胞中经历显著上调。此外，在低水平叶酸的存在下，PSMA表达增加了细胞侵袭性，这是一种对肿瘤形成和进展都很重要的活性。我们的假设是：低，其次是过量水平的可用叶酸在前列腺在很长一段时间内导致致癌作用。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，和（B）在新的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增加PSMA的侵袭能力，并导致基因组低甲基化、DNA不稳定性和随后的致癌作用，和3）确定，在前列腺癌发生开始之前，补充叶酸是保护性的，并且如果在开始之后，补充叶酸通过增强由PSMA介导的前列腺中的全身叶酸的摄取以及通过改变表观遗传编程来促进前列腺肿瘤生长和进展。相关性：最近的报告描述了叶酸补充剂和前列腺癌之间的显着关联。1998年U.S.diet的叶酸强化已经将人口从叶酸缺乏转变为叶酸充足。研究表明，过量摄入叶酸会增加患乳腺癌、结肠直肠癌和前列腺癌的风险。我们已经表明，近200万60岁或以上的男性血清叶酸水平超过5倍。这一事实，结合临床前前列腺癌在>60岁年龄组男性中的高患病率，强调了研究叶酸与前列腺癌之间关系的重要性。