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: 7888825
• 负责人: Dean John Bacich
• 金额: $ 33.14万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888825
• 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; Complement component C1s; 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; Figs - dietary; 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; 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 cell; 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; polyglutamate; polyglutamates; pre-clinical; prevent; programs; promoter; prostate carcinogenesis; protective effect; public health relevance; research study; response; tumor; tumor growth; tumor initiation; 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. PUBLIC HEALTH RELEVANCE: These studies have the potential to yield important information regarding both the safety of, and the potentially protective effects, of folic acid supplementation on prostate carcinogenesis and progression, and are particularly timely given the recent mandatory fortification of the American diet with folic acid. Dietary folate intake is an easily modifiable factor; prostate cancer is a slow growing disease - even if we can effect only a modest increase in time to progression via dietary folate intake, it could result in a large clinical impact. If we understand how dietary folate manipulation can alter DNA methylation patterns, and how the effect of folate may be modulated by PSMA expression, we may be able to detect and provide nutritional or chemo- intervention to men at-risk for prostate cancer, preventing or delaying the disease.

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) 叶酸水平是否在新型体内模型中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，并导致基因组低甲基化、DNA 不稳定和随后的致癌作用，以及 3) 在前列腺癌发生之前确定叶酸是否存在 补充叶酸具有保护作用，如果开始补充叶酸后，通过增强 PSMA 介导的前列腺对全身叶酸的摄取以及改变表观遗传编程，从而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。 公共健康相关性：这些研究有可能提供有关补充叶酸对前列腺癌发生和进展的安全性和潜在保护作用的重要信息，鉴于最近美国饮食中叶酸的强制强化，这些研究显得尤为及时。 膳食叶酸摄入量是一个容易改变的因素；前列腺癌是一种生长缓慢的疾病 - 即使我们只能通过膳食叶酸摄入来适度延长进展时间，它也可能会产生巨大的临床影响。 如果我们了解膳食叶酸操作如何改变 DNA 甲基化模式，以及叶酸的作用如何通过 PSMA 表达进行调节，我们也许能够检测出前列腺癌高危男性并为其提供营养或化学干预，从而预防或延缓该疾病。