Dietary Folate: Impact on Prostate Tumor Biology, Genetics and Epigenetics

描述(由申请人提供)： 过去十年的流行病学研究表明，饮食中叶酸(维生素B9)的摄入量与患肝癌和肠癌的风险呈负相关。叶酸在一种碳代谢中起核心作用，并通过促进dNTP的生物合成而显著影响DNA合成。叶酸还通过促进S腺苷蛋氨酸的生物合成来影响DNA甲基化，腺苷蛋氨酸是DNA甲基转移酶使用的甲基供体分子。前列腺上皮细胞对这些代谢途径提出了异常高的要求，因为这些细胞中的多胺分解代谢水平非常高，SAM是通过脱羧基被从系统中取出的。已知这些途径的缺陷会导致遗传损伤以及以全局低甲基化和CpG岛特异性高甲基化的形式出现的表观遗传损害。我们假设，前列腺对饮食中叶酸的操纵非常敏感，因为它对叶酸所在的代谢途径的要求异常高。此外，我们预测，改变饮食叶酸可以通过影响对肿瘤形成过程至关重要的遗传和表观遗传损伤来影响前列腺癌(CAP)的肿瘤发生进展。我们将通过改变转基因小鼠前列腺癌(TRAMP)模型中的饮食叶酸来验证这一假设，该模型发展为类似于男性CAP的进展期前列腺疾病。我们将测试饮食控制叶酸(与对照饮食相比，消耗和补充叶酸)对前列腺上皮生长和表型的影响。此外，我们将在遗传和表观遗传水平上研究这些过程背后的分子机制。我们的研究结果将使我们能够建立饮食叶酸操纵和驱动前列腺上皮肿瘤发生的遗传/表观遗传损伤之间的机制关系。CAP是一种生长缓慢的恶性肿瘤，通常在疾病开始和临床症状出现之间表现出很长的滞后期。饮食控制叶酸可能提供一种有效的工具来延缓和控制从惰性状态到高度攻击性状态的CAP进展。这样的饮食工具可能会导致帽子死亡率的大幅下降，使患者能够与非侵袭性疾病生活在一起。与公共健康相关：前列腺癌是美国男性最常见的癌症。这项建议将在小鼠模型中研究饮食叶酸缺乏和补充对前列腺癌生物学的影响。我们预测，补充剂将通过支持前列腺细胞中需要叶酸的超负荷代谢途径来降低基因组完整性受损的速度。如果是这样的话，这可能会对男性前列腺癌产生非常重要的影响，使我们能够减缓前列腺癌最初出现迹象的男性的进展，从而显著降低这种疾病的死亡率。

DESCRIPTION (provided by applicant): Epidemiologic studies over the past decade suggest an inverse association of dietary folate (vitamin B9) intake with the risk of cancers of the liver and intestine. Folate plays a central role in one carbon metabolism and significantly impacts DNA synthesis by contributing to dNTP biosynthesis. Folate also impacts DNA methylation by contributing to biosynthesis of S-adenosylmethionine (SAM), the methyl donor molecule used by DNA methyltransferases. Prostate epithelial cells place an unusually high demand on these metabolic pathways because SAM is pulled from the system by decarboxylation due to the extraordinarily high level of polyamine catabolism in these cells. Deficiencies in these pathways are known to cause genetic damage as well as epigenetic damage in the form of global hypomethylation and CpG island specific hypermethylation. We hypothesize that the prostate is exquisitely sensitive to manipulation of folate in the diet due to its unusually high demand on the metabolic pathways folate is central to. Furthermore, we predict that altering dietary folate can influence the tumorigenic progression in prostate cancer (CaP) by influencing the genetic and epigenetic damage critical to the tumorigenic process. We will test this hypothesis by altering the dietary folate in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model that develops progressive stages of prostatic disease similar to CaP in men. We will test how dietary manipulation of folate (both depletion and supplementation compared to control diet) will affect prostate epithelium growth and phenotype. Further, we will investigate the molecular mechanisms underlying these processes at the genetic and epigenetic level. The results of our study will allow us to establish a mechanistic relationship between dietary folate manipulation and the genetic/epigenetic damage that drives tumorigenesis in prostatic epithelium. CaP arises as a slow-growing malignancy typically exhibiting a long lag period between initiation of disease and presentation of clinical symptoms. Dietary manipulation of folate might provide an effective tool to delay and control CaP progression from an indolent state to a highly aggressive state. Such a dietary tool could result in a major decrease in CaP mortality allowing patients to live with a non-aggressive disease. PUBLIC HEALTH RELEVANCE: Cancer of the prostate is the most commonly diagnosed cancer in American men. This proposal will study the effect of dietary folate deficiency and supplementation on the biology of prostate cancer in a mouse model. We predict that supplementation will reduce the rate at which the integrity of the genome is compromised by buttressing the over-burdened metabolic pathways requiring folate in prostate cells. If so, this could have very important implications for prostate cancer in men allowing us to slow the progression in men showing the very first signs of prostate cancer and therefore significantly reducing mortality from this disease.