Comparative Mechanisms of Cancer Chemoprevention

描述（由申请人提供）：NIH 路线图规定表观遗传学是研究重点。与癌症相关的遗传变化不同，表观遗传变化是可能可以改变的，并且饮食因素已被证明可以“解除抑制”癌细胞中表观遗传沉默的基因，从而引发细胞周期停滞和细胞凋亡。该 P01 的总体长期目标是更好地了解膳食制剂带来有益表观遗传变化的机制，识别和表征可应用于临床的表观遗传生物标志物，并在临床前和转化研究中评估这些生物标志物。 凭借三个整合良好的项目和一个互补的表观遗传/转化生物标志物核心，这一竞争性的延续通过比较机制、生物标志物和临床前模型（淋巴瘤、前列腺癌、结肠癌、肺癌）解决膳食吲哚和异硫氰酸盐在癌症干预中的应用（和可能的风险），从而在人类志愿者中进行表观遗传生物标志物的转化研究。 中心假设是萝卜硫素 (SFN) 和吲哚-3-甲醇 (ISC) 以及它们的来源十字花科蔬菜是有效的化学预防剂，因为除了它们在起始阶段的阻断活性之外，它们还改变癌细胞中组蛋白修饰（乙酰化、甲基化、磷酸化）和组蛋白脱乙酰酶 (HDAC) 活性的模式，以及 DNA 启动子甲基化状态，从而去抑制调节细胞周期和细胞凋亡的表观遗传沉默基因。 E. Ho 将研究“前列腺癌的化学预防、HDAC 抑制和 DNA 甲基化”（项目 1），D.E. Williams 将研究“肺肿瘤和淋巴瘤的经胎盘化学预防”（项目 2），R.H. Dashwood 将研究“结肠癌的化学预防、HDAC 抑制和组蛋白状态”（项目 3）。这项工作的总体意义在于，它旨在为结肠癌、前列腺癌、肺癌以及淋巴瘤的预防和治疗提供新的表观遗传学见解，这些癌症一直被列为美国癌症相关死亡的首要原因。该应用在连接基本机制、临床前模型以及表观遗传学和饮食的人体研究方面具有创新性和及时性。

DESCRIPTION (provided by applicant): The NIH Roadmap stipulates that epigenetics is a research priority. Unlike genetic changes associated with cancer, epigenetic changes are potentially modifiable, and dietary factors have been shown to "de-repress" epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. The overall long-term objectives of this P01 are to better understand the mechanisms by which beneficial epigenetic changes can be brought about by dietary agents, to identify and characterize epigenetic biomarkers that can be applied in the clinical setting, and to evaluate those biomarkers in preclinical and translational studies. With three well-integrated Projects and a complementary Epigenetic/Translational Biomarkers Core, this competing continuation addresses the application (and possible risks) of dietary indoles and isothiocyanates for cancer intervention, through comparative mechanism, biomarker, and preclinical models (lymphoma, prostate, colon, lung cancer), leading to translational studies of epigenetic biomarkers in human volunteers. The CENTRAL HYPOTHESIS is that sulforaphane (SFN) and indole-3-carbinol (ISC), and the cruciferous vegetables from which they derive, are effective chemopreventive agents because, in addition to their blocking activities during the initiation phase, they alter the pattern of histone modifications (acetylation, methylation, phosphorylation) and histone deacetylase (HDAC) activity in cancer cells, as well as DNA promoter methylation status, thereby de-repressing epigenetically silenced genes that regulate the cell cycle and apoptosis. E. Ho will investigate "Chemoprevention of prostate cancer, HDAC inhibition, and DNA methylation" (Project 1), D.E. Williams will study "Transplacental chemoprevention of lung tumors and lymphomas" (Project 2), and R.H. Dashwood will examine "Chemoprevention of colon cancer, HDAC inhibition, and histone status" (Project 3). The overall significance of the work is that it seeks to provide new epigenetic insights into the prevention and treatment of colon, prostate, and lung cancer, as well as lymphoma, which are listed consistently among the top causes of cancer-related deaths in the US. This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet.