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

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.