Gene Methylation Targets for Prostate Cancer Prevention by Early Soy Exposure

描述（申请人提供）：美国和西方国家的前列腺癌（PCa）发病率远高于亚洲。高大豆消费已被提议降低PCa风险。然而，最近的流行病学研究没有发现西方人群中大豆饮食对PCa预防的健康益处的证据。到目前为止，我们仍然没有一个明确的图片的作用，大豆可能发挥预防PCa。考虑到亚洲婴儿的大豆暴露水平高于美国婴儿，以及动物研究中早期大豆暴露对PCa预防的增强，人们认为大豆暴露的时间可能是西方与亚洲人群中大豆对PCa保护结果不同的一个因素。染料木黄酮（GEN），一种主要的大豆黄酮，在生命早期给予时会改变DNA甲基化。然而，尚不清楚早期大豆暴露是否调节前列腺中的基因甲基化，从而降低以后生活中的PCa风险。拟议研究的目标是调查早期膳食大豆蛋白摄入的表观遗传基础，重点是确定可能介导PCa预防保护作用的基因甲基化靶点。我们假设GEN，特别是在生命早期给予时，在前列腺中通过预防或纠正癌前病变形成期间的异常DNA甲基化变化而充当“甲基化组看护者”。提出了两个具体目标：目标1：确定GEN补充的时间对前列腺上皮内瘤变（PIN）化学预防功效的影响。目标二：通过早期暴露于饮食GEN来识别和表征PIN预防的基因甲基化靶点。在目的1中，我们将使用大鼠模型来评估GEN对预防PIN的性激素诱导的化学预防功效，PIN被认为是PCa前体。我们预测，终身GEN暴露，怀孕后开始，是更有效的比GEN暴露限制在成年期。在目标2中，我们建议使用高通量甲基化阵列和集成的生物信息学来识别签名基因甲基化标记，这些标记可以作为分子介质或生物标志物，用于增强对早期大豆消费的PCa预防。我们还将使用基于知识的方法来确定早期大豆暴露对前列腺癌风险评估的潜在甲基化标志物的影响。我们将确定候选基因的发育重编程是否发生在生命周期GEN方案的早期。这项提案的发现应该会增强我们对饮食、表观遗传学和癌症预防之间关系的理解。这一建议可能会开始一个新的研究方向，调查大豆暴露的时间和表观遗传学是否是决定饮食大豆干预PCa结果的关键因素。 公共卫生相关性：关于大豆饮食对预防前列腺癌的健康益处有相当大的争论。有证据表明，大豆暴露对西方人群预防前列腺癌的作用有限。拟议的工作试图解决一个关键问题，即大豆暴露的最佳时机是否可以提高其化学预防功效，这些发现可能会导致更好的大豆干预设计，以提高其对前列腺癌的有效性。

DESCRIPTION (provided by applicant): The incidence of prostate cancer (PCa) in the US and Western countries is much higher than that in Asia. High soy consumption has been proposed to reduce PCa risk. However, recent epidemiologic studies did not find evidence for health benefits of soy diet on PCa prevention in Western populations. To date, we still do not have a clear picture of the role that soy may play in PCa prevention. Given higher soy exposure levels found in Asian infants than American infants, and enhancement of PCa prevention with early soy exposure in animal studies, it is thought that timing of soy exposure may be a factor for the differing outcomes of soy's protection against PCa in Western versus Asian populations. Genistein (GEN), a major soy isoflavone, alters DNA methylation when given early in life. However, it remains unknown if the early soy exposure modulates gene methylation in the prostate gland, thereby reducing PCa risk later in life. The goal of the proposed research is to investigate the epigenetic basis of early dietary soy isoflavone intake, with a focus on identifying the gene methylation targets that may mediate the protective effects on PCa prevention. We hypothesize that GEN, especially when given early in life, serves as a "methylome caretaker" in the prostate by preventing or rectifying aberrant DNA methylation changes during the onset of precancereous lesion formation. Two specific aims are proposed: Aim 1: Determine the effects of timing of GEN supplementation on the efficacy of chemoprevention against Prostate Intraepithelial Neoplasia (PIN). Aim 2: Identify and characterize gene methylation targets for PIN prevention by early exposure to dietary GEN. In Aim 1, we will use a rat model to evaluate the chemopreventive efficacy of GEN on preventing sex hormone induction of PIN, which is believed to be PCa precursor. We predict that lifelong GEN exposure, started after conception, is more effective than GEN exposure limited in adulthood. In aim 2, we propose to use high throughput methylation arrays and integrated bioinformatics to identify signature gene methylation marks that may serve as molecular mediators or biomarkers for the enhancement of PCa prevention in response to early soy consumption. We will also use a knowledge-based approach to determine the effects of early soy exposure on potential methylation markers for prostate cancer risk assessment. We will determine if developmental reprogramming of the candidate genes occurs early in the life-time GEN regimen. Findings from this proposal should enhance our understanding of the relationships between diet, epigenetics and cancer prevention. This proposal may embark on a new research direction to investigate if timing of soy exposure and epigenetics as critical factors determining the outcome of dietary soy intervention on PCa. PUBLIC HEALTH RELEVANCE: There has been considerable debate regarding the health benefits of soy diet on prostate cancer prevention. Evidence suggests that soy exposure has limited effects to prevent prostate cancer in Western populations. The proposed work attempts to address a key issue of whether optimal timing of soy exposure may enhance its chemopreventive efficacy and the findings may lead to a better-design of soy intervention to increase its effectiveness against prostate cancer.