Abstract 5191: Dual roles for CDK8 in cancer and stem cell maintenance

Abstract Cyclin Dependent Kinase 8 (CDK8) is a highly conserved member of the Mediator complex that is required for animal development and growth. Several groups have recently identified CDK8 as a colorectal oncogene (Firestein R., et al Nature 2008; Starr T. Science 2009). While, loss of CDK8 expression inhibits colon cancer cell line proliferation in vitro, the mechanism through which this occurs is unkown. In order to examine the role of CDK8 on tumor growth in vivo, we generated inducible knockdown cell lines in two colon cancer cell line models. We find that CDK8 is necessary for tumor progression in vivo and loss of CDK8 imparts a differentiated phenotype in xenografted colon cancer tumors. FACS analysis of these tumors shows that loss of CDK8 leads to a specific depletion of the tumor initating stem cell compartment. These observations were extended to mouse and human intestine, where CDK8 protein levels were found to be increased both in tumors and in the basal portion of the crypt where the intestinal stem cells reside To further explore the mechanism by which CDK8 leads to this depletion, we performed both microarray gene expression analysis and whole genome ChIP to identify CDK8 transcriptional targets. We find that many of CDK8 regulated targets overlap with gene signatures known to be upregulated in stem cells (p<1×10−45). To determine the relevance of these transcriptional targets to colon cancer, we assessed their level of expression in colon tumors and performed a loss of function screen in a panel of 12 cell lines to determine which genes are required for colon cancer proliferation. Using this approach we identify a subset of CDK8 downstream genes with dual roles in cancer and embryonic maintenance. These data show that modulation of CDK8 induces differentiation in cancer cells by potentially targeting the stem cell properties of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5191. doi:10.1158/1538-7445.AM2011-5191