Abstract
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.
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Acknowledgements
We thank E. Shin for technical assistance with immunohistochemistry, M. Miri for assistance with sample collection and G. Getz for assistance with SNP array analysis. This work was supported in part by a grant from the US NCI/NIH R33CA128625 (W.C.H.), T32 NIH grant (R.F.) and a GI SPORE Career Development Grant (P50CA127003; R.F.), a Harvard-MIT Clinical Investigator Training Program Fellowship (A.J.B), Department of Defense Prostate Cancer Postdoctoral Fellowships (I.G. and S.Y.K.), Warren-Whitman-Richardson, Hagerty Foundation Research Fellowships (I.F.D.) and K12 award (M.G.C.). J.B. is a Beatriu de Pinos Fellow of the Departament d’Educació i Universitats de la Generalitat de Catalunya.
Author Contributions R.F., A.J.B., M.M. and W.C.H. designed the approach. R.F., A.J.B., E.B., E.F., I.F.D., I.G., J.S.B., N.V., S.J.S., S.O., S.Y.K. and Y.S. performed the experiments. J. Barretina, J. Baselga, J.T. and R.A.S. provided samples and analysis. A.H.L., A.J.B., C.M., C.S.F., D.E.R., E.B., E.F., I.F.D., I.G., J.A.C., M.G.C., M.L., M.M., P.T., R.A.S., R.F., S.F., S.J.S., S.O., S.Y.K. and W.C.H. analysed data. R.F., A.J.B., R.A.S. and W.C.H. wrote the manuscript.
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In accordance with Harvard Medical School guidelines, we disclose that W.C.H., M.M., M.L. and R.A.S. are consultants for Novartis.
Additional information
The SNP data can be found at http://research3.dfci.harvard.edu/cdk8colon/index.php.
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Firestein, R., Bass, A., Kim, S. et al. CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature 455, 547–551 (2008). https://doi.org/10.1038/nature07179
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