Mechanisms of Epigenetic Gene Silencing

描述（由申请人提供）：表观遗传学改变有助于肿瘤进展的所有阶段，并且众所周知，生长控制基因和肿瘤抑制基因的异常DNA甲基化和组蛋白低乙酰化直接有助于恶性肿瘤。由于表观遗传变化是可逆的，这些改变代表了有前途的新抗癌药物的有吸引力的目标，这一特性最近已被开发用于新的治疗方法。虽然最近的进展导致FDA批准了前两种“表观遗传疗法”，但对其疗效的机制基础知之甚少。这项提议将探索一类相对未被探索的脱乙酰酶（sirtuins）和在基因沉默中与甲基化DNA结合的蛋白质（甲基-CpG结合蛋白）之间的全新联系。这些进展可以帮助解释为什么一些实体瘤对目前的表观遗传疗法是难治的，并提供一个更完整的机制，使肿瘤抑制基因（TSGs）在遗传上沉默。 阐明这种生长控制基因和TSGs的表观遗传沉默的分子基础对于鉴定新的抗癌疗法是重要的，我们建议做以下工作：具体目标1 -确定甲基-CpG结合蛋白在靶向SIRT 1内源性高甲基化基因启动子中的作用。具体目标2 -确定甲基-CpG结合蛋白和SIRT 1在沉默的生长控制和肿瘤抑制基因中调节染色质结构的作用。具体目标3 -通过SIRT 1确定MeCP 2乙酰化和脱乙酰化的功能意义。 公共卫生相关性：由于多种HDAC抑制剂处于临床试验的不同阶段，因此了解脱乙酰酶如何促进肿瘤发生是很重要的，我们已经确定了去乙酰酶sirtuin家族在肿瘤抑制基因沉默中的新作用。

DESCRIPTION (provided by applicant): Epigenetic alterations contribute to all stages of tumor progression and it is well recognized that aberrant DNA methylation and histone hypoacetylation of growth control genes and tumor suppressor genes directly contribute to malignancy. Because epigenetic changes are reversible, these alterations represent attractive targets for promising new anticancer agents and this property has been exploited recently for new therapies. While recent progress has lead to the FDA approval of the first two "epigenetic therapies" the mechanistic basis for their efficacy is poorly understood. This proposal will explore entirely new links between a relatively unexplored class of deacetylases (the sirtuins) and proteins that bind to methylated DNA (methyl-CpG binding proteins) in gene silencing. These advances could help explain why some solid tumors are refractory to the current epigenetic therapies and provide a more complete mechanism by which tumor suppressor genes (TSGs) become heritably silenced. Elucidating the molecular basis for this epigenetic silencing of growth control genes and TSGs is important for identifying novel anticancer therapies and we propose to do the following: Specific Aim 1 - Determine the role of methyl-CpG binding proteins in targeting SIRT1 to endogenous hypermethylated gene promoters. Specific Aim 2 - Determine the contribution of methyl-CpG binding proteins and SIRT1 in regulating chromatin structure at silenced growth control and tumor suppressor genes. Specific Aim 3 - Determine the functional significance of MeCP2 acetylation and deacetylation by SIRT1. PUBLIC HEALTH RELEVANCE: Because multiple HDAC inhibitors are in various phases of clinical trials, it is important to understand how deacetylases contribute to tumorigenesis, and we have identified a novel role for the sirtuin family of deacetylases in tumor suppressor gene silencing.