Investigations on the role of the CDK8 oncogene in colon cancer

CDK8癌基因在结肠癌中的作用研究

• 批准号: 8204832
• 负责人: William C. Hahn
• 金额: $ 39.12万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204832
• 关键词: APC gene; Adenomatous Polyposis Coli; Affect; Air; Biochemical; Biochemical Genetics; Biological; Biology; Breast; Cancer Model; Carcinoma; Cell Proliferation; Cell physiology; Cells; Chemicals; Colon; Colon Carcinoma; Colorectal Cancer; Complex; Development; Diagnosis; Disease; Embryonic Development; Epithelial; Event; Experimental Models; Foundations; Future; Gene Targeting; Genetic; Genetic Transcription; Genome; Germ-Line Mutation; Goals; Growth; Human; Human Development; Investigation; Ligands; Liver; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Mutation; Nuclear; Oncogenes; Oncogenic; Ovarian; Pathogenesis; Pathway interactions; Phosphotransferases; Play; Prostate; Regulation; Role; Signal Pathway; Signal Transduction; Staging; Stem cells; Therapeutic; Therapeutic Agents; Tumor Suppressor Genes; Work; base; cancer genome; cancer initiation; cell transformation; colon cancer cell line; functional genomics; inhibitor/antagonist; insight; novel; novel therapeutics; overexpression; public health relevance; receptor; small molecule; therapeutic target; tool; translational study; tumor; tumor progression; tumorigenesis

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.

描述（申请人提供）：Wnt/β-连环蛋白调控的通路在几乎所有结肠癌中都发挥着重要作用。 APC 种系突变的遗传会导致结肠癌综合征、家族性腺瘤性息肉病 (FAP)，并且在几乎所有自发性结直肠癌中都会发生 ¡-连环蛋白突变（通过 ¡-连环蛋白突变或更常见的是由于 APC 抑癌基因缺失）导致 ¡-连环蛋白通路异常激活。 β-连环蛋白的致癌激活也与其他癌症有关，例如乳腺癌、卵巢癌、前列腺癌和肝癌。尽管现在已知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、β-连环蛋白信号的扩增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癌症基因组的持续结构表征相结合来鉴定新型人类致癌基因的综合努力的一部分，我们发现CDK8（介体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子集中被扩增和过表达，是具有CDK8拷贝数增益的结肠癌细胞系增殖所必需的，并调节 用于 ¿-连环蛋白依赖性转录活性。 CDK8 的强制表达会诱导细胞转化，并且 CDK8 激酶活性对于 β-连环蛋白依赖性诱导转化是必需的。这些观察结果将 CDK8 确定为结肠癌癌基因，参与 WNT/¿-catenin 通路的调节。 基于这些观察，本提案重点研究 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β-连环蛋白中的作用，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，这些研究将为靶向该激酶癌基因的治疗策略奠定基础。 公共卫生相关性：尽管在结肠癌的诊断和治疗方面取得了重大进展，但我们缺乏针对大多数晚期结肠癌的治疗性靶向治疗。该提案的重点是破译新发现的癌基因在结肠癌发生和进展中的作用。这些生化、细胞和化学生物学研究不仅将提供对该激酶癌基因生物学的深入了解，而且将作为开发新型治疗剂的转化研究的基础。