CDK8 Mediator kinase drives colon cancer hepatic metastasis by regulating gene expression of the matrix metalloproteinase network [Affymetrix]. Mus musculus

CDK8 Mediator kinase is amplified and overexpressed in colon cancers; elevated CDK8 expression is associated with shorter patient survival. Nevertheless, CDK8 kinase inhibitors do not generally suppress colon cancer growth. We addressed this paradox by investigating the effects of CDK8 knockdown or a CDK8 kinase inhibitor on tumor growth at primary and metastatic sites. CDK8 knockdown or inhibition had no significant effect on primary tumors but suppressed the growth of hepatic metastases in murine and human colon cancer models. The effect of CDK8 inhibition on liver metastasis is mediated by upregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 and downregulation of several MMPs. Overall design: Microarray analysis comparing CT26 cells treated with DMSO and 5 µM Senexin B for 24 h and the comparison between CT26-pLKO.1 and CT26-shCDK8 were performed using Affymetrix Mouse gene 2.0 X ST arrays by the Functional Genomics Core of the Center for Targeted Therapeutics at the University of South Carolina.