The function of Snf5, an epigenetic tumor suppressor

描述(由申请人提供)：大多数癌症，如果不是全部，都有表观遗传学变化，这被认为有助于肿瘤的发生。然而，很难评估表观遗传变化在基因组不稳定背景下的贡献。SNF5(INI1/SMARCB1/BAF47)在侵袭性人类癌症和家族性癌症易感综合征中特异突变。在之前的资助期间，我们发现SNF5缺失不会影响DNA修复或染色体稳定性，但会迅速导致侵袭性癌症，这些癌症缺乏基因组的不稳定性，并具有广泛的表观遗传学改变。虽然已经假设SNF5的缺失会导致SWI/SNF复合体的失活，但我们有更多的证据表明，肿瘤的发生更多地是由残留复合体的异常激活引起的。事实上，SNF5缺陷的癌症由于伴随着SWI/SNF复合体的核心ATPase BRG1的丧失而被消灭。这一建议将利用实验室开发的独特试剂来检验我们的假设，即SNF5缺失引起的癌症是由部分功能SWI/SNF复合体的新形态效应引起的特定启动子上的核小体位置失调所致，我们还将确定与SNF5缺失协同作用的表观遗传调控途径。目的1：Snf5失活对核小体定位有何影响？目的2：Snf5缺失对SWI/SNF复合体的靶向和组成有何影响？目的3：在致癌转化过程中，哪些基因与Snf5缺失有协同作用？意义：SWI/SNF复合体在多种人类癌症中发生突变。还没有研究评估SNF5在核小体重塑或靶向SWI/SNF复合体的基本活动中的作用。拟议的实验将提供对正常SWI/SNF功能的洞察，定义在没有基因组不稳定的情况下破坏表观遗传调节因子导致侵袭性、致命性癌症快速发作的机制，并确定新的基于表观遗传的治疗干预靶点。 公共卫生相关性：SNF5和SWI/SNF染色质重塑复合体的其他亚单位在各种侵袭性人类癌症和家族性癌症综合征中特定突变。拟议的实验将提供对正常SWI/SNF功能的洞察，确定破坏该复合体导致侵袭性、致命性癌症快速发作的机制，并确定治疗干预的新靶点。

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. PUBLIC HEALTH RELEVANCE: SNF5 and other subunits of the SWI/SNF chromatin remodeling complex are specifically mutated in a variety of aggressive human cancers and in a familial cancer syndrome. The proposed experiments will provide insight into normal Swi/Snf function, define a mechanism by which disruption of this complex causes the rapid onset of aggressive, lethal cancers and identify novel targets for therapeutic intervention.