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.
Firestein
Ron
R
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Bass
Adam J
AJ
Kim
So Young
SY
Dunn
Ian F
IF
Silver
Serena J
SJ
Guney
Isil
I
Freed
Ellen
E
Ligon
Azra H
AH
Vena
Natalie
N
Ogino
Shuji
S
Chheda
Milan G
MG
Tamayo
Pablo
P
Finn
Stephen
S
Shrestha
Yashaswi
Y
Boehm
Jesse S
JS
Jain
Supriya
S
Bojarski
Emeric
E
Mermel
Craig
C
Barretina
Jordi
J
Chan
Jennifer A
JA
Baselga
Jose
J
Tabernero
Josep
J
Root
David E
DE
Fuchs
Charles S
CS
Loda
Massimo
M
Shivdasani
Ramesh A
RA
Meyerson
Matthew
M
Hahn
William C
WC
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D034622:RNA Interference; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
D015513:Oncogene Proteins; D051176:beta Catenin; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases
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