The function of Snf5, an epigenetic tumor suppressor

表观遗传肿瘤抑制因子 Snf5 的功能

• 批准号: 8676680
• 负责人: CHARLES ROBERTS
• 金额: $ 31.69万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676680
• 关键词: ATP phosphohydrolase; Affect; Benign; Binding; Cancer Etiology; Cells; Chromatin; Chromatin Remodeling Factor; Chromosomal Stability; Complementary DNA; Complex; Custom; DNA Binding; DNA Repair; Disease; Epigenetic Process; Funding; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic Instability; Genomics; Goals; Hereditary Malignant Neoplasm; Human; In Vitro; Individual; Laboratories; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mus; Mutate; Nucleosomes; Oncogenic; Pathway interactions; Pattern; Positioning Attribute; Predisposition; Process; Reagent; Residual state; Role; SMARCA4 gene; SMARCB1 gene; Syndrome; Testing; Therapeutic Intervention; Tumor Suppression; Tumor Suppressor Proteins; Variant; base; cancer cell; insight; novel; promoter; research study; small hairpin RNA; therapeutic target; transcription factor; tumorigenesis

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.

描述（由申请人提供）：大多数（如果不是全部）癌症都有表观遗传变化，这些变化提出有助于造成肿瘤。但是，很难评估基因组不稳定性环境中表观遗传变化的贡献。 SNF5（INI1/SMARCB1/BAF47）在侵略性的人类癌症和家族性癌症易感综合征中特异性突变。在上一个资金期间，我们发现SNF5损失不会影响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且具有广泛表观遗传改变的侵略性癌症。尽管已经假设SNF5导致SWI/SNF复合物失活，但我们还有其他证据表明肿瘤发生是由于残留复合物的异常激活而引起的。实际上，SNF5缺陷型癌症被BRG1的损失（SWI/SNF复合物的核心ATPase）消除。该提案将利用实验室中开发的独特试剂，以检验我们的假设，即由SNF5损失引起的癌症是由功能障碍的核小体位置驱动的，这是由特定启动子的特定启动子造成的，这是由部分功能性SWI/SNF复合物的新形态效应引起的，我们还将确定与SNF5损失合作的表观遗传调节的途径。 AIM 1：SNF5失活对核小体定位的影响是什么？ AIM 2：SNF5损失对SWI/SNF复合物的靶向和组成有什么影响？ AIM 3：哪些基因在致癌转化中与SNF5损失合作？意义：SWI/SNF复合物在各种人类癌症中被突变。尚无研究评估SNF5在SWI/SNF复合物的基本活动中的核小体重塑或靶向。提出的实验将提供对正常SWI/SNF功能的洞察力，定义了一种机制，通过这种机制，表观遗传调节剂的破坏会导致在缺乏基因组不稳定性的情况下快速发作，致命的癌症的迅速发作，并识别出新型的表观遗传学靶标，用于治疗干预。