Investigations on the role of the CDK8 oncogene in colon cancer

描述（由申请人提供）：Wnt/¿-catenin调控的通路在几乎所有结肠癌中都起着重要作用。APC种系突变的遗传驱动结肠癌综合征，家族性腺瘤性息肉病（FAP），并且-catenin途径的异常激活通过-catenin突变或更常见的是APC肿瘤抑制基因的缺失发生在几乎所有自发的结直肠癌中。-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。虽然这一信号通路的许多组成部分现在已经知道，但调节这一途径的机制及其在癌症进展中的作用仍然不完全清楚。在最近的研究中，我们发现了CDK8和catenin信号的扩增与结肠癌之间的联系。作为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结构表征相结合来鉴定新型人类癌基因的综合努力的一部分，我们发现CDK8，中介复合物的一个组成部分，在人类结肠癌细胞系和肿瘤的大量亚群中被扩增和过表达，这是结肠癌细胞系增殖所必需的，这些细胞系具有CDK8拷贝数的增加。并调节依赖连环蛋白的转录活性。强迫表达CDK8诱导细胞转化，CDK8激酶活性是¿-catenin依赖性诱导转化所必需的。这些观察结果表明CDK8是参与WNT/¿-catenin通路调控的结肠癌致癌基因。基于这些观察结果，本研究将重点研究CDK8在结肠癌发病机制中的作用。具体来说，将应用生化、遗传、分子生物学和药理学方法来阐明CDK8在调节-catenin中的作用，以确定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在结肠癌发展中的作用不仅将增强我们对这种新致癌基因的机制理解，还将阐明中介复合物在人类上皮癌发展中的作用。此外，这些研究将为靶向该激酶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. PUBLIC HEALTH RELEVANCE: Although significant progress has been made in the diagnosis and treatment of colon cancer, we lack curative targeted therapies for most advanced stage colon cancers. This proposal focuses on deciphering the role of a newly discovered oncogene in colon cancer initiation and progression. These biochemical, cell and chemical biological studies will not only provide insight into the biology of this kinase oncogene but will serve as a foundation for translational studies for the development of novel therapeutic agents.