CDK8 is a colorectal cancer oncogene that regulates β-catenin activity

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Abstract
The WNT/ β-catenin signalling pathway, which normally plays a pivotal part in development, is deregulated in almost all colorectal cancers. Retinoblastoma tumour suppressor protein (pRB) is a cell-cycle regulator that is mutated in many different types of cancer. Two papers in this issue show that signalling through the WNT pathway and that mediated by pRB are highly interconnected, and that a common denominator of their deregulation is colorectal cancer. Firestein et al. combined RNAi screening for genes required for colon cancer cell proliferation with genomic data from human colon cancer to identifty CDK8 as a novel human oncogene. CDK8, a general transcriptional regulator, functions in part by enhancing the activity of the Wnt signalling pathway. Morris et al. report that E2F1, a transcription factor that is a target of pRB, is a potent and specific inhibitor of β-catenin, and that its activity is negatively regulated by CDK8. They point out that the interaction between E2F1 and β-catenin explains the long-standing paradox that pRB, an important tumour suppressor in most other contexts, is preserved in colorectal carcinomas. In an accompanying News & Views, René Bernards considers how the crosstalk between E2F and β-catenin signalling can lead to colorectal cancer. Aberrant activation of the canonical WNT/β-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival1,2. Although dysregulated β-catenin activity drives colon tumorigenesis, further genetic perturbations are required to elaborate full malignant transformation3. To identify genes that both modulate β-catenin activity and are essential for colon cancer cell proliferation, we conducted two loss-of-function screens in human colon cancer cells and compared genes identified in these screens with an analysis of copy number alterations in colon cancer specimens. One of these genes, CDK8, which encodes a member of the mediator complex4, is located at 13q12.13, a region of recurrent copy number gain in a substantial fraction of colon cancers. Here we show that the suppression of CDK8 expression inhibits proliferation in colon cancer cells characterized by high levels of CDK8 and β-catenin hyperactivity. CDK8 kinase activity was necessary for β-catenin-driven transformation and for expression of several β-catenin transcriptional targets. Together these observations suggest that therapeutic interventions targeting CDK8 may confer a clinical benefit in β-catenin-driven malignancies.