Deregulation of COMPASS complex and enhancer chromatin in pancreatic cancer

项目摘要 胰腺癌是美国癌症相关死亡的第四大常见原因， 5年生存率低于10%虽然它的特点是少数定义明确的 遗传改变，例如KRAS癌基因以及TP 53、CDKN 2A和SMAD 4的突变 肿瘤抑制剂，但以这些途径为靶点的努力一直不成功。在 相比之下，驱动胰腺癌的表观遗传网络在分子水平上知之甚少。 水平和未开发的治疗目标。表观遗传改变经历选择压力，驱动 肿瘤进展，并导致突变和拷贝数的改变，染色质修饰 内切酶考虑到重新连接的表观遗传电路不存在于正常细胞中，但在细胞中是必不可少的。 癌症，识别和靶向负责的酶可能会发现一个致命的弱点， 为患者量身定制的治疗方法。X染色体编码组蛋白KDM 6A的突变 去甲基酶，KMT 2C和KMT 2D甲基转移酶在胰腺癌中是常见的，并定义了 一个具有不同组织学和预后差的亚组。KDM 6A、KMT 2C和KMT 2D是 COMPASS（与Set 1相关的蛋白质复合物）-样复合物，使组蛋白单甲基化 H3 K4以界定增强子染色质。长延伸的增强子染色质形成“超级增强子” 其优先调节协调细胞命运和谱系定型决定的基因。我们 发现COMPASS复合体中的突变重新连接“超级增强子”，以消除身份， 低分化和侵袭性肿瘤的发展。此外，KDM 6A的损失表现出 小鼠中的性别特异性肿瘤抑制作用，雌性小鼠发生不同的鳞状细胞癌肿瘤 和准间充质组织学。使用小分子文库的高通量筛选 抑制剂揭示了COMPASS复合突变胰腺癌对溴结构域敏感， 末端外（BET）结构域家族的抑制剂，这表明可以利用的治疗利基 用于个性化治疗。在这里，我们产生了基因工程小鼠和人类细胞系， 有条件地删除Kdm 6a、Kmt 2c和Kmt 2d，并建议（a）全面研究 COMPASS复合物在胰腺癌的发生和发展中的作用，（B）绘制胰腺癌的表观遗传图谱。 改变增强子染色质以促进胰腺肿瘤发生，以及（c）鉴定和靶向 表观遗传脆弱性源于COMPASS复合体的丧失。

PROJECT SUMMARY Pancreatic cancer is the fourth most common cause of cancer related deaths in the United States with a 5-year survival rate less than 10%. Although it is characterized by a small number of well-defined genetic alterations, such as mutations of the KRAS oncogene as well as TP53, CDKN2A, and SMAD4 tumor suppressors, efforts to pharmacologically target those pathways have been unsuccessful. In contrast, the epigenetic networks that drive pancreatic cancer are poorly understood at the molecular level and unexplored as therapeutic targets. Epigenetic alterations undergo selective pressure, drive neoplastic progression, and result from mutations and copy number alterations in chromatin modifying enzymes. Considering that rewired epigenetic circuitries are not present in normal cells, yet essential in cancer, identification and targeting the responsible enzymes may uncover an Achilles’ heel for the development of patient tailored therapies. Mutations in KDM6A, an X chromosome encoded histone demethylase, and KMT2C and KMT2D methyltransferases are frequent in pancreatic cancer and define a subgroup with distinct histology and dismal prognosis. KDM6A, KMT2C, and KMT2D are part of a COMPASS (COMplex of Proteins ASsociated with Set1)-like complex which mono-methylates histone H3K4 to delimit enhancer chromatin. Long stretches of enhancer chromatin form “super-enhancers” which preferentially regulate genes that orchestrate cell fate and lineage commitment decisions. We found that mutations in the COMPASS complex rewire “super-enhancers” to erase identity and favor the development of poorly differentiated and aggressive tumors. Furthermore, loss of KDM6A exhibits a gender specific tumor suppressor role in mice, with females developing distinct tumors of squamous and quasi-mesenchymal histology. High-throughput screening using a library of small molecule inhibitors revealed that COMPASS complex mutant pancreatic cancer is sensitive to Bromodomain and Extra-Terminal (BET) domain family of inhibitors, suggesting a therapeutic niche that can be exploited for personalized therapies. Here, we generated genetically engineered mice and human cell lines to conditionally delete Kdm6a, Kmt2c, and Kmt2d and propose to (a) comprehensively study the role of COMPASS complex in the initiation and progression of pancreatic cancer, (b) map the epigenetic changes that rewire enhancer chromatin to facilitate pancreatic oncogenesis, and (c) identify and target epigenetic vulnerabilities stemming from loss of COMPASS complex.