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

Ron Firestein, Adam J. Bass, So Young Kim, Ian F. Dunn, Serena J. Silver, Isil Guney, Ellen Freed, Azra H. Ligon, Natalie Vena, Shuji Ogino, Milan G. Chheda, Pablo Tamayo, Stephen Finn, Yashaswi Shrestha, Jesse S. Boehm, Supriya Jain, Emeric Bojarski, Craig Mermel, Jordi Barretina, Jennifer A. ChanJose Baselga, Josep Tabernero, David E. Root, Charles S. Fuchs, Massimo Loda, Ramesh A. Shivdasani, Matthew Meyerson, William C. Hahn

Research output: Contribution to journalArticlepeer-review

513 Scopus citations

Abstract

Aberrant activation of the canonical WNT/β-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Although dysregulated β-catenin activity drives colon tumorigenesis, further genetic perturbations are required to elaborate full malignant transformation. 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 complex, 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.

Original languageEnglish
Pages (from-to)547-551
Number of pages5
JournalNature
Volume455
Issue number7212
DOIs
StatePublished - Sep 25 2008

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