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

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

Pubmed ID: 18794900


  • Firestein R
  • Bass AJ
  • Kim SY
  • Dunn IF
  • Silver SJ
  • Guney I
  • Freed E
  • Ligon AH
  • Vena N
  • Ogino S
  • Chheda MG
  • Tamayo P
  • Finn S
  • Shrestha Y
  • Boehm JS
  • Jain S
  • Bojarski E
  • Mermel C
  • Barretina J
  • Chan JA
  • Baselga J
  • Tabernero J
  • Root DE
  • Fuchs CS
  • Loda M
  • Shivdasani RA
  • Meyerson M
  • Hahn WC



Publication Data

September 25, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: K08 CA134931
  • Agency: NCI NIH HHS, Id: P50CA127003
  • Agency: NCI NIH HHS, Id: R33 CA128625
  • Agency: NCI NIH HHS, Id: R33 CA128625-01A1
  • Agency: NCI NIH HHS, Id: R33CA128625
  • Agency: NCI NIH HHS, Id: T32 CA009172
  • Agency: NIGMS NIH HHS, Id: T32 GM007753

Mesh Terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Colorectal Neoplasms
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Oncogene Proteins
  • Oncogenes
  • RNA Interference
  • Transcription, Genetic
  • beta Catenin