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的优先事项。与癌症相关的遗传变化不同，表观遗传变化是潜在的可改变的，而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，引发细胞周期停滞和细胞凋亡。P01的总体长期目标是更好地了解饮食制剂可以带来有益的表观遗传变化的机制，识别和表征可应用于临床环境的表观遗传生物标记物，并在临床前和翻译研究中评估这些生物标记物。 通过三个整合良好的项目和一个互补的表观遗传/翻译生物标记物核心，这一竞争继续进行，通过比较机制、生物标记物和临床前模型(淋巴瘤、前列腺癌、结肠癌、肺癌)，解决饮食吲哚和异硫氰酸酯在癌症干预中的应用(和可能的风险)，导致在人类志愿者中进行表观遗传生物标记物的翻译研究。 中心假说是萝卜硫醚(SFN)和吲哚-3-甲醇(ISC)及其衍生的十字花科蔬菜是有效的化学预防药物，因为除了它们在起始阶段的阻断活性外，它们还改变了癌细胞中组蛋白修饰(乙酰化、甲基化、磷酸化)和组蛋白脱乙酰基酶(HDAC)活性的模式，以及DNA启动子甲基化状态，从而抑制了表观遗传沉默的调控细胞周期和细胞凋亡的基因。 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“通过胎盘的化学预防肺癌和淋巴瘤”(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，它寻求为预防和治疗结肠癌、前列腺癌和肺癌以及淋巴瘤提供新的表观遗传学见解，在美国，这些癌症一直被列为与癌症相关的死亡的首要原因。这一应用在连接基本机制、临床前模型以及人类表观遗传学和饮食研究方面是创新和及时的。

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.