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Nature 455, 547-551 (25 September 2008) | doi:10.1038/nature07179; Received 30 March 2008; Accepted 19 June 2008; Published online 14 September 2008

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CDK8 is a colorectal cancer oncogene that regulates bold beta-catenin activity

Ron Firestein1,2,6,7, Adam J. Bass1,3,6,7, So Young Kim1,3,6,7, Ian F. Dunn1,4,6,7, Serena J. Silver7, Isil Guney1,6,7, Ellen Freed1, Azra H. Ligon2, Natalie Vena1, Shuji Ogino1,2, Milan G. Chheda1,5,7, Pablo Tamayo7, Stephen Finn2, Yashaswi Shrestha1,6,7, Jesse S. Boehm7, Supriya Jain1, Emeric Bojarski1, Craig Mermel1,6,7, Jordi Barretina1,6,7, Jennifer A. Chan2,7, Jose Baselga8, Josep Tabernero8, David E. Root7, Charles S. Fuchs1, Massimo Loda1,2, Ramesh A. Shivdasani1,3, Matthew Meyerson1,2,6,7 & William C. Hahn1,3,6,7

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
  2. Department of Pathology,
  3. Department of Medicine and,
  4. Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  5. Department of Neuro-oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
  6. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
  7. Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
  8. Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain

Correspondence to: William C. Hahn1,3,6,7 Correspondence and requests for materials should be addressed to W.C.H. (Email: william_hahn@dfci.harvard.edu).

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Aberrant activation of the canonical WNT/beta-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival1, 2. Although dysregulated beta-catenin activity drives colon tumorigenesis, further genetic perturbations are required to elaborate full malignant transformation3. To identify genes that both modulate beta-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 beta-catenin hyperactivity. CDK8 kinase activity was necessary for beta-catenin-driven transformation and for expression of several beta-catenin transcriptional targets. Together these observations suggest that therapeutic interventions targeting CDK8 may confer a clinical benefit in beta-catenin-driven malignancies.

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
  2. Department of Pathology,
  3. Department of Medicine and,
  4. Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  5. Department of Neuro-oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
  6. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
  7. Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
  8. Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain

Correspondence to: William C. Hahn1,3,6,7 Correspondence and requests for materials should be addressed to W.C.H. (Email: william_hahn@dfci.harvard.edu).