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PMID: 18794900 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Nature ·Vol. 455 ·No. 7212 ·2008-09-25 ·Pages 547-51

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

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.

MeSH Terms
Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic Colorectal Neoplasms/genetics,metabolism,pathology Cyclin-Dependent Kinase 8 Cyclin-Dependent Kinases/deficiency,genetics,metabolism Gene Dosage Gene Expression Regulation, Neoplastic Humans Oncogene Proteins/deficiency,genetics,metabolism Oncogenes RNA Interference Transcription, Genetic beta Catenin/metabolism
Chemicals
Oncogene Proteins beta Catenin CDK8 protein, human Cyclin-Dependent Kinase 8 Cyclin-Dependent Kinases
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Firestein Ron
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Bass Adam J
Kim So Young
Dunn Ian F
Silver Serena J
Guney Isil
Freed Ellen
Ligon Azra H
Vena Natalie
Ogino Shuji
Chheda Milan G
Tamayo Pablo
Finn Stephen
Shrestha Yashaswi
Boehm Jesse S
Jain Supriya
Bojarski Emeric
Mermel Craig
Barretina Jordi
Chan Jennifer A
Baselga Jose
Tabernero Josep
Root David E
Fuchs Charles S
Loda Massimo
Shivdasani Ramesh A
Meyerson Matthew
Hahn William C
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature07179
Published
2008-09-25
Epub
2008-00-14
Pages
547-51
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2587138
Subset
IM
Grants
NCI NIH HHS · R33 CA128625 · United States
NCI NIH HHS · K08 CA134931 · United States
NIGMS NIH HHS · T32 GM007753 · United States
NCI NIH HHS · T32 CA009172 · United States
NCI NIH HHS · R33 CA128625-01A1 · United States
NCI NIH HHS · P50CA127003 · United States
NCI NIH HHS · R33CA128625 · United States
NCI NIH HHS · P50 CA127003 · United States
Corrections
CommentIn
PMID: 18818647
External Links
PubMed source DOI: 10.1038/nature07179 PMC Full Text View journal details
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