Role of the SWI/SNF complex in tumor suppression

项目概要/摘要： 癌症基因组测序研究现在已经揭示，编码9种不同亚基的基因， SWI/SNF染色质重塑复合物在多种人类癌症中经常突变。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 血总的来说，超过20%的人类癌症含有SWI/SNF突变， 复合了癌症中最常突变的染色质/表观遗传调节因子。在目前的资金 我们在阐明SWI/SNF复合物的功能方面取得了显著进展。然而，少校 随后出现了一些问题。SWI/SNF复合物由核心亚基和变体亚基组成， 后者仅存在于复合物的子类中。现在已经很清楚，频繁变异的 亚基均为变体亚基，包括ARID 1A、SMARCA 4和PBRM 1，且每个亚基突变均 与不同的癌症谱相关。然而，这些机制和功能的贡献， 对SWI/SNF功能的变异亚基和亚类了解甚少。我们假设肿瘤发生 不是由于SWI/SNF复合物功能的广泛丧失，而是由于残余的 SWI/SNF复合物。我们进一步假设，变异肿瘤抑制亚单位的丢失改变了肿瘤细胞的功能。 SWI/SNF的组成、靶向和染色质重塑活性，从而损害分化， 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 三个目的：目的1：SWI/SNF复合物的互斥ATP酶亚基SMARCA 4/BRG 1 和SMARCA 2/BRM，在功能上不同，SMARCA 2合成致死的机制基础是什么 SMARCA 4突变型癌症目的2：含PBRM 1的PBAF亚类SWI/SNF复合物 在组成、靶向、染色质重塑方面与含ARID 1A/B的BAF亚类不同 活性、增强子调控和谱系特化的控制？目标3：我们新发现的BRD 9- 包含的子类在组成和功能上与其他SWI/SNF子类不同，BRD 9可以是 被当作治疗目标吗

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?