Analysis of the role of the SWI/SNF complex in tumor suppression

描述(由申请人提供)：新出现的数据表明SWI/SNF染色质重塑复合体是主要的肿瘤抑制因子。在过去的[两年]里，大量的癌症基因组测序研究表明，在各种人类癌症中，至少有六个亚单位被特异性地高频失活，包括卵巢癌、乳腺癌、肾癌、肺癌、胰腺癌、子宫癌、膀胱癌、胃癌、结肠癌、肝脏[和皮肤癌]。SWI/SNF复合体包括核心亚基和谱系特异性亚基，并利用ATP的能量来调节染色质结构。我的实验室已经通过基因敲除小鼠模型的产生，证明了其中一个亚基具有强大而真实的肿瘤抑制作用。为了深入了解机制，我们最近证实了SWI/SNF和Polycomb复合体之间存在表观遗传拮抗作用。然而，SWI/SNF复合体对体内染色质结构的贡献以及为什么每个亚单位与不同的癌症光谱相关的原因仍然知之甚少。鉴于在每个亚基中发现了独特的染色质靶向和修饰结构域，我们假设肿瘤发生是由于残存的SWI/SNF复合体的差异定位错误和它们的染色质重塑活性受损所致。我们进一步假设，SWI/SNF亚单位突变会导致谱系特异性基因表达程序的中断，这是由于与Polycomb PRC2复合体的不平衡表观遗传拮抗引起的。通过以下特定的目标，我们的目标是确定SWI/SNF复合体的亚单位如何对染色质结构做出贡献，建立肿瘤抑制亚单位突变导致癌症形成的机制，确定肿瘤抑制亚基与PRC2复合体之间的表观遗传拮抗程度，并寻找新的有效的SWI/SNF突变癌症的治疗靶点：目标1：单个SWI/SNF肿瘤抑制亚基的缺失如何影响SWI/SNF复合体的DNA结合、染色质重塑活性和完整性，以及它们的缺失如何影响基因表达？目的2：残存的SWI/SNF复合体在SWI/SNF肿瘤抑制亚基突变所致的肿瘤中起什么作用？目的3：SWI/SNF突变导致的多梳状复合体与肿瘤的关系是什么？意义：鉴于越来越多的癌症被发现含有SWI/SNF亚单位的突变，这种复合体现在出现了与人类疾病有重大关联的情况。通过提出的特定靶点验证我们的假说，有可能阐明正常SWI/SNF复合体的功能，建立SWI/SNF肿瘤抑制亚基突变导致癌症形成的机制，并确定各种SWI/SNF突变癌症的治疗靶点。

DESCRIPTION (provided by applicant): Emerging data implicate the SWI/SNF chromatin remodeling complex as a major tumor suppressor. Over the past [two years], numerous cancer genome sequencing studies have revealed that at least six subunits of the complex are specifically inactivated at high frequency in a variety of human cancers including those of ovary, breast, kidney, lung, pancreas, uterus, bladder, stomach, colon, liver [and skin]. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure. My laboratory has demonstrated a potent and bona fide tumor suppressor role for one of the subunits through generation of a knockout mouse model. Providing some insight into mechanism, we have recently established the existence of epigenetic antagonism between SWI/SNF and Polycomb complexes. However, the contributions of the SWI/SNF complex to chromatin structure in vivo and the reasons why each subunit is associated with distinct cancer spectra remain poorly understood. Given the unique chromatin targeting and modification domains found in each subunit, we hypothesize that oncogenesis occurs due to differential mistargeting of residual SWI/SNF complexes and impairment of their chromatin remodeling activity. We further hypothesize that SWI/SNF subunit mutations cause disruption of lineage-specific gene expression programs arising from imbalanced epigenetic antagonism with the Polycomb PRC2 complex. Via the following specific aims, our goals are to determine how the subunits of the SWI/SNF complex contribute to chromatin structure, to establish the mechanism by which mutation of the tumor suppressor subunits drives cancer formation, to determine the extent of epigenetic antagonism between the tumor suppressor subunits and the PRC2 complex, and to identify novel and effective therapeutic targets for SWI/SNF mutant cancers: Aim 1: How does loss of individual SWI/SNF tumor suppressor subunits affect the DNA binding, chromatin remodeling activity, and integrity of the SWI/SNF complex, and how does their loss affect gene expression? Aim 2: What is the role of the residual SWI/SNF complex in cancers driven by mutation of SWI/SNF tumor suppressor subunits? Aim 3: What is the relationship between Polycomb complexes and cancers that are driven by SWI/SNF mutations? Significance: Given the increasingly wide spectrum of cancers being found to contain mutations in SWI/SNF subunits, the complex now emerges as having major relevance for human disease. Testing our hypotheses via the proposed specific aims has the potential to elucidate the function of the normal SWI/SNF complex, establish the mechanisms by which mutation of SWI/SNF tumor suppressor subunits drive cancer formation, and identify therapeutic targets for the wide variety of SWI/SNF mutant cancers.