Investigations on the role of the CDK8 oncogene in colon cancer

描述(申请人提供)：由Wnt/？-catenin调控的通路在几乎所有结肠癌中都起着重要的作用。APC中胚系突变的遗传导致结肠癌综合征、家族性腺瘤性息肉病(FAP)，以及通过β-连环蛋白突变或更常见的通过丢失APC抑癌基因而导致的β-连环蛋白途径的异常激活，几乎在所有自发呼吸的结直肠癌中都会发生。连环蛋白的致癌激活也与其他癌症有关，如乳腺癌、卵巢癌、前列腺癌和肝癌。尽管目前已知道该信号通路的许多组成部分，但调节该通路的机制及其在癌症进展中的作用仍不完全清楚。在最近的工作中，我们发现CDK8的扩增和连环蛋白信号与结肠癌之间存在联系。作为通过将高通量功能基因组方法与人类细胞转化的实验模型和正在进行的癌症基因组的结构特征相结合来确定新的人类癌基因的全面努力的一部分，我们发现CDK8是介体复合体的一个组成部分，在人类结肠癌细胞系和肿瘤的相当一部分中被扩增和过表达，对于具有CDK8拷贝数增加的结肠癌细胞系的增殖是必需的，并调节连环蛋白依赖的转录活性。CDK8的强制表达可诱导细胞转化，而CDK8的激活是连环蛋白依赖性诱导转化所必需的。这些观察结果表明，CDK8是一个结肠癌癌基因，参与了WNT/β-连环蛋白途径的调节。基于这些观察，本建议重点研究CDK8在结肠癌发病机制中的作用。具体地说，将应用生化、遗传学、分子生物学和药理学方法来阐明CDK8在调节连环蛋白中的作用，识别参与细胞转化的其他CDK8靶点，并验证CDK8作为潜在的治疗靶点。研究CDK8在结肠癌发生发展中的作用不仅将增强我们对这一新的癌基因的机制的了解，而且还将阐明该介体复合体在人类上皮性癌症发生中的作用。此外，这些研究将为针对这种癌基因的治疗策略提供基础。

DESCRIPTION (provided by applicant): The pathway regulated by Wnt/¿-catenin plays an important role in nearly all colon cancers. Inheritance of a germline mutation in APC drives the colon cancer syndrome, Familial Adenomatous Polyposis (FAP), and aberrant activation of the ¿-catenin pathway either through mutation of ¿-catenin or more commonly by loss of the APC tumor suppressor gene occurs in almost all spontaneously airing colorectal cancers. Oncogenic activation of ¿-catenin has also been implicated in other cancers such as breast, ovarian, prostate and liver carcinomas. Although many of the components of this signaling pathway are now known, the mechanisms that regulate this pathway and its role in cancer progression remain incompletely understood. In recent work, we have found a connection between amplifications of CDK8, ¿-catenin signaling and colon cancer. As part of a comprehensive effort to identify novel human oncogenes by integrating high throughput functional genomic approaches with experimental models of human cell transformation and on-going structural characterization of cancer genomes, we found that CDK8, a component of the Mediator complex, is amplified and overexpressed in a substantial subset of human colon cancer cell lines and tumors, is required for the proliferation of colon cancer cell lines that harbor CDK8 copy number gain, and regulates for ¿-catenin-dependent transcriptional activity. Forced expression of CDK8 induces cell transformation, and CDK8 kinase activity is necessary for ¿-catenin-dependent induced transformation. These observations identify CDK8 as a colon cancer oncogene that participates in the regulation of WNT/¿-catenin pathway. Based on these observations, this proposal focuses on investigating the role of CDK8 in colon cancer pathogenesis. Specifically, biochemical, genetic, molecular biological and pharmacologic approaches will be applied to elucidate the role of CDK8 in regulating ¿-catenin, to identify other CDK8 targets that participate in cell transformation and to validate CDK8 as a potential therapeutic target. Investigating the role of CDK8 in colon cancer development will not only enhance our mechanistic understanding of this new oncogene but will also clarify the role of the Mediator complex in the development of human epithelial cancers. In addition, these studies will provide a foundation for strategies to target this kinase oncogene therapeutically.