Gene Methylation Targets for Prostate Cancer Prevention by Early Soy Exposure

描述(申请人提供)：前列腺癌(PCA)在美国和西方国家的发病率远远高于亚洲。高大豆消费量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没有发现大豆饮食对西方人群预防前列腺癌的健康益处的证据。到目前为止，我们仍然不清楚大豆在预防前列腺癌中可能发挥的作用。鉴于亚洲婴儿中发现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加强了对PCA的预防，人们认为大豆暴露的时间可能是西方和亚洲人群中大豆预防PCa结果不同的一个因素。染料木素(Genistein，GEN)是一种主要的大豆异黄酮，在生命早期服用时会改变DNA甲基化。然而，目前尚不清楚早期接触大豆是否调节了前列腺中的基因甲基化，从而降低了以后生活中的前列腺癌风险。这项拟议研究的目的是调查早期饮食大豆异黄酮摄入的表观遗传学基础，重点是识别可能介导保护作用的基因甲基化靶点，以预防前列腺癌。我们假设，Gen，特别是在生命早期给予Gen，通过防止或纠正癌前病变形成过程中异常的DNA甲基化变化，在前列腺中起到“甲基组看守者”的作用。提出了两个特定的目标：目标1：确定基因补充的时机对前列腺癌(PIN)化学预防效果的影响。目的2：确定和表征通过早期饮食基因暴露来预防PIN的基因甲基化靶点。在目标1中，我们将使用一个大鼠模型来评价GEN对防止性激素诱导的PIN的化学预防效果，PIN被认为是前列腺癌的前体。我们预测，在受孕后开始终身接触Gen，比成年后有限的Gen接触更有效。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标志性基因甲基化标记，这些标记可以作为分子介体或生物标记物来加强对早期大豆消费的PCA的预防。我们还将使用基于知识的方法来确定早期接触大豆对前列腺癌风险评估的潜在甲基化标记物的影响。我们将确定候选基因的发育重新编程是否发生在终身基因方案的早期。这项建议的发现应该会加强我们对饮食、表观遗传学和癌症预防之间关系的理解。这一建议可能会开启一个新的研究方向，调查大豆暴露的时机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，一直存在相当大的争论。有证据表明，在西方人群中，接触大豆对预防前列腺癌的效果有限。这项拟议的工作试图解决一个关键问题，即最佳的大豆暴露时间是否可以增强其化学预防效果，这一发现可能会导致更好地设计大豆干预措施，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.