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

Abstract:

: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.

journal_name

Nature

journal_title

Nature

authors

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,

doi

10.1038/nature07179

subject

Has Abstract

pub_date

2008-09-25 00:00:00

pages

547-51

issue

7212

eissn

0028-0836

issn

1476-4687

pii

nature07179

journal_volume

455

pub_type

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