Gene Methylation Targets for Prostate Cancer Prevention by Early Soy Exposure

描述（由申请人提供）：前列腺癌（PCa）在美国和西方国家的发病率远高于亚洲。大量食用大豆被认为可以降低前列腺癌的风险。然而，最近的流行病学研究并没有发现大豆饮食对西方人群预防前列腺癌有益的证据。到目前为止，我们对大豆在预防前列腺癌中的作用还没有一个清晰的认识。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预防的增强作用，人们认为大豆暴露的时间可能是大豆在西方和亚洲人群中预防PCa的不同结果的一个因素。染料木素（GEN）是一种主要的大豆异黄酮，如果在生命早期服用，会改变DNA甲基化。然而，尚不清楚早期大豆接触是否会调节前列腺基因甲基化，从而降低以后患前列腺癌的风险。该研究的目的是研究早期膳食大豆异黄酮摄入的表观遗传学基础，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，通过预防或纠正癌前病变形成期间异常的DNA甲基化变化，在前列腺中充当“甲基化看守者”。提出了两个具体目标：目标1：确定补充GEN的时间对化学预防前列腺上皮内瘤变（PIN）疗效的影响。目的2：确定并表征早期暴露于膳食GEN预防PIN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对防止性激素诱导PIN（被认为是PCa前体）的化学预防效果。我们预测，怀孕后开始的终身GEN暴露比成年期有限的GEN暴露更有效。在目标2中，我们建议使用高通量甲基化阵列和集成生物信息学来识别可能作为分子介质或生物标志物的特征基因甲基化标记，以增强早期大豆消费对PCa的预防作用。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中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终生GEN方案的早期。这项建议的发现将增强我们对饮食、表观遗传学和癌症预防之间关系的理解。这一建议可能开启一个新的研究方向，探讨大豆暴露时间和表观遗传学是否是决定膳食大豆干预前列腺癌结果的关键因素。

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.