Role of epigenetic regulators in pancreatic cancer

项目概要/摘要 真核基因转录受染色质修饰的影响，这些修饰受表观遗传调控。 调节蛋白除了遗传改变，现在很明显，表观遗传机制也是 癌症发病机制的核心。表观遗传改变是可遗传的，驱动肿瘤进展，并经历 和基因改变一样的选择压力。因此，确定关键的表观遗传调节因子， 癌症应该指向新的和更好的治疗方法。一种综合的生物学方法已经被 用于识别和剖析组蛋白修饰酶家族在发育中的作用， 胰腺导管腺癌（PDAC）是美国第四大常见的癌症死亡原因。 这种无偏见的遗传筛选导致了jumonji结构域组蛋白去甲基化酶（HDMs）家族的发现 作为PDAC的重要监管者。特别地，已经发现HDM，KDM 2B，是高度稳定的。 在PDAC中上调，并且是PDAC细胞系的致瘤性和永生化所需的， 原代细胞的转化。通过使用获得和丧失功能的方法和基因工程 我们提出小鼠模型来描述KDM 2B参与PDAC的分子机制 通过定义关键靶基因和建立功能性相互作用来启动、进展和维持 KDM 2B和其他染色质修饰酶之间的关系。鉴于组蛋白甲基化的可逆性， Jumonji结构域KDM 2B的重要性-与许多其他致癌转录调节因子不同- 代表了开发小分子抑制剂的有吸引力的候选者。

Project summary/Abstract Eukaryotic gene transcription is influenced by chromatin modifications that are under the control of epigenetic regulatory proteins. In addition to genetic alterations, it is now apparent that epigenetic mechanisms are also central to cancer pathogenesis. Epigenetic alterations are heritable, drive neoplastic progression, and undergo the same selective pressure as genetic alterations. Therefore identifying the key epigenetic regulators in cancers should point to new and better therapeutic approaches. An integrative biology approach has been employed to identify and dissect the role that families of histone modifying enzymes play in the development of pancreatic ductal adenocarcinoma (PDAC), the 4th most common cause of cancer death in the United States. This unbiased genetic screen led the discovery of the family of jumonji-domain histone demethylases (HDMs) as important regulators of PDAC. In particular, it has been found that the HDM, KDM2B, was highly upregulated in PDAC and was required for the tumorigenicity of PDAC cell lines and the immortalization and transformation of primary cells. By using gain- and loss-of-function approaches and genetically engineered mouse models we propose to delineate the molecular mechanisms by which KDM2B contributes to PDAC initiation, progression, and maintenance by defining key target genes and establishing the functional interaction between KDM2B and other chromatin modifying enzymes. Given the reversibility of histone methylation and the importance of the Jumonji domain, KDM2B -unlike many other oncogenic transcriptional regulators- represents an attractive candidate for the development of small molecule inhibitors.