Investigations on the role of the CDK8 oncogene in colon cancer

描述（由申请人提供）：由Wnt/β-连环蛋白调节的途径在几乎所有结肠癌中起重要作用。APC中的生殖系突变的遗传驱动结肠癌综合征、家族性腺瘤性息肉病（FAP），并且通过<$-连环蛋白突变或更常见地通过APC肿瘤抑制基因的丢失而发生的<$-连环蛋白途径的异常激活发生在几乎所有自发性结肠直肠癌中。连环蛋白的致癌激活也与其他癌症如乳腺癌、卵巢癌、前列腺癌和肝癌有关。虽然现在已经知道了这种信号通路的许多组成部分，但调节这种通路的机制及其在癌症进展中的作用仍然不完全清楚。 在最近的工作中，我们发现了CDK 8，ω-连环蛋白信号的扩增和结肠癌之间的联系。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癌症基因组的持续结构表征相结合来鉴定新型人类癌基因的全面努力的一部分，我们发现CDK 8，介体复合物的一种组分，在人类结肠癌细胞系和肿瘤的大量亚群中扩增和过表达，是携带CDK 8拷贝数增加的结肠癌细胞系增殖所必需的，并调节β-连环蛋白依赖性转录活性。CDK 8的强制表达诱导细胞转化，并且CDK 8激酶活性对于β-连环蛋白依赖性诱导的转化是必需的。这些观察结果将CDK 8鉴定为参与WNT/β-连环蛋白途径调节的结肠癌基因。 基于这些观察结果，本提案重点研究CDK 8在结肠癌发病机制中的作用。具体而言，生物化学，遗传学，分子生物学和药理学方法将被应用于阐明CDK 8在调节β-连环蛋白中的作用，以鉴定参与细胞转化的其他CDK 8靶点，并验证CDK 8作为潜在的治疗靶点。研究CDK 8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，而且还将阐明介体复合物在人类上皮癌发展中的作用。此外，这些研究将为治疗靶向这种激酶癌基因的策略提供基础。 公共卫生相关性：虽然结肠癌的诊断和治疗已经取得了重大进展，但我们缺乏针对大多数晚期结肠癌的治愈性靶向治疗。这项提案的重点是破译一个新发现的癌基因在结肠癌发生和发展中的作用。这些生物化学，细胞和化学生物学研究不仅将提供深入了解这种激酶癌基因的生物学，但将作为一个基础，为开发新的治疗药物的翻译研究。

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.