The function of Snf5, an epigenetic tumor suppressor

描述（由申请人提供）：大多数（如果不是全部的话）癌症具有表观遗传变化，这被认为有助于肿瘤发生。然而，很难评估表观遗传变化在基因组不稳定性中的作用。SNF 5（INI 1/SMARCB 1/BAF 47）在侵袭性人类癌症和家族性癌症易感综合征中特异性突变。在之前的资助期间，我们发现SNF 5的丢失不会影响DNA修复或染色体稳定性，但会迅速导致缺乏基因组不稳定性并具有广泛表观遗传改变的侵袭性癌症。虽然已经假设SNF 5丢失导致SWI/SNF复合物的失活，但我们有额外的证据表明肿瘤发生是由残余复合物的异常激活引起的。事实上，SNF 5缺陷型癌症通过伴随的BRG 1（SWI/SNF复合物的核心ATP酶）的损失而消除。该提案将利用实验室开发的独特试剂来测试我们的假设，即SNF 5损失引起的癌症是由部分功能性SWI/SNF复合物的新形态效应引起的特定启动子处的功能失调的核小体位置驱动的，我们还将鉴定与SNF 5损失合作的表观遗传调节途径。 目的1：Snf 5失活对核小体定位有什么影响？ 目的2：Snf 5缺失对Swi/Snf复合物的靶向和组成有什么影响？ 目的3：哪些基因与Snf 5的缺失在致癌转化中协同作用？意义：Swi/Snf复合物在多种人类癌症中发生突变。没有研究评估SNF 5在核小体重塑或靶向中的作用，SWI/SNF复合物的基本活性。拟议的实验将提供对正常Swi/Snf功能的深入了解，定义一种机制，通过该机制，在没有基因组不稳定性的情况下，表观遗传调节因子的破坏会导致侵袭性、致命性癌症的快速发作，并确定新的基于表观遗传的治疗干预靶点。

DESCRIPTION (provided by applicant): Most, if not all, cancers have epigenetic changes, which are proposed to contribute to oncogenesis. However, it is difficult to evaluate the contribution of epigenetic changes in the setting of genome instability. SNF5 (INI1/SMARCB1/BAF47) is specifically mutated in aggressive human cancers and in a familial cancer predisposition syndrome. In the previous funding period we found that SNF5 loss does not affect DNA repair or chromosome stability but rapidly leads to aggressive cancers that lack genome instability and possess widespread epigenetic alterations. While it has been hypothesized that SNF5 loss leads to inactivation of the SWI/SNF complex, we have additional evidence that tumorigenesis is rather caused by aberrant activation of the residual complex. Indeed, SNF5-deficient cancers are abolished by concomitant loss of BRG1, the core ATPase of the SWI/SNF complex. This proposal will exploit unique reagents developed in the laboratory to test our hypothesis that cancer caused by SNF5 loss is driven by dysfunctional nucleosome position at specific promoters caused by neomorphic effects of a partially functional SWI/SNF complex and we will also identify the epigenetically regulated pathways that cooperate with SNF5 loss. Aim 1: What are the effects of Snf5 inactivation upon nucleosome positioning? Aim 2: What are the effects of Snf5 loss upon the targeting and composition of the Swi/Snf complex? Aim 3: What genes cooperate with Snf5 loss in oncogenic transformation? Significance: The Swi/Snf complex is mutated in a variety of human cancers. No studies have evaluated the role of SNF5 in nucleosome remodeling or targeting, fundamental activities of the SWI/SNF complex. The proposed experiments will provide insight into normal Swi/Snf function, define a mechanism by which disruption of an epigenetic regulator causes the rapid onset of aggressive, lethal cancers in the absence of genome instability and identify novel epigenetically based targets for therapeutic intervention.