Role of the SWI/SNF complex in tumor suppression

项目摘要/摘要： 癌症基因组测序研究现已揭示，编码九个不同亚基的基因 SWI/SNF染色质重塑复合体在多种人类癌症中经常发生突变。这些 包括脑癌、卵巢癌、乳腺癌、肾癌、肺癌、胰腺癌、子宫癌、膀胱癌、胃癌、结肠癌、肝癌、皮肤癌和 血。总体而言，超过20%的人类癌症含有SWI/SNF突变，使SWI/SNF 复合体是癌症中最常发生突变的染色质/表观遗传调节因子。在目前的资助期间 我们在阐明SWI/SNF复合体的功能方面取得了显着的进展。然而，梅杰 随后出现了一些问题。SWI/SNF复合体由核心亚单位和变异亚基组成， 而后者仅存在于复合体的子类中。现在已经很清楚了，频繁突变的 亚基都是变异亚基，包括ARID1A、SMARCA4和PBRM1，且每个亚基的突变都是 与不同的癌症谱相关联。然而，这些技术在机制和功能上的贡献 SWI/SNF功能的变异亚基和亚类知之甚少。我们假设肿瘤的发生 发生不是由于SWI/SNF复合功能的广泛丧失，而是由于残差功能的异常 SWI/SNF复合体。我们进一步假设，变异的肿瘤抑制亚基的丢失改变了 SWI/SNF的组成、靶向和染色质重塑活性从而损害分化和 促进肿瘤发生。使用我们的基因工程原代细胞、细胞系和小鼠，我们将解决 三个目标：目标1：SWI/SNF复合体中相互排斥的ATPase亚单位SMARCA4/BRG1是如何 和SMARCA2/BRM在功能上的不同以及SMARCA2综合致死性的机制基础是什么 在SMARCA4突变癌症中？目标2：含有PBRM1的PBAF亚类SWI/SNF复合体是如何 在成分、靶向、染色质重塑方面与含ARID1A/B的BAF亚类不同 血统规范的活性、增强子调控？目标3：我们新发现的BRD9是如何- 包含的子类在组成和功能上与其他SWI/SNF子类不同，并且BRD9可以 被用作治疗目标？

Project Summary/Abstract: Cancer genome sequencing studies have now revealed that genes that encode nine different subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in a wide variety of human cancers. These include cancers of brain, ovary, breast, kidney, lung, pancreas, uterus, bladder, stomach, colon, liver, skin and blood. Collectively, over twenty percent of all human cancers contain a SWI/SNF mutation making SWI/SNF complexes the most frequently mutated chromatin/epigenetic regulator in cancer. During the current funding cycle we have made notable progress in elucidating the functions of SWI/SNF complexes. However, major questions have subsequently emerged. SWI/SNF complexes consist of both core subunits and variant subunits, with the latter present in only sub-classes of complexes. It has now become clear that the frequently mutated subunits are all variant subunits including ARID1A, SMARCA4 and PBRM1 and that mutation of each is associated with a distinct cancer spectrum. However, the mechanistic and functional contributions of these variant subunits and sub-classes to SWI/SNF function is poorly understood. We hypothesize that oncogenesis occurs not due to broad loss of SWI/SNF complex function but rather due to aberrant function of residual SWI/SNF complexes. We further hypothesize that loss of the variant tumor-suppressor subunits alters the composition, targeting and chromatin remodeling activity of SWI/SNF thus impairing differentiation and promoting oncogenesis. Using our genetically engineered primary cells, cell lines and mice, we will address three aims: Aim 1: How do the mutually exclusive ATPase subunits of SWI/SNF complexes, SMARCA4/BRG1 and SMARCA2/BRM, differ in function and what is the mechanistic basis for the synthetic lethality of SMARCA2 in SMARCA4 mutant cancers? Aim 2: How does the PBRM1-containig PBAF sub-class of SWI/SNF complexes differ from the ARID1A/B-containing BAF sub-class with respect to composition, targeting, chromatin remodeling activity, enhancer regulation and control of lineage specification? Aim 3: How does our newly discovered BRD9- containing sub-class differ in composition and function from other SWI/SNF sub-classes, and can BRD9 be exploited as a therapeutic target?