title: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
authors.forename: Serena J
authors.initials: SJ
authors.lastname: Silver
authors.forename: Isil
authors.initials: I
authors.lastname: Guney
authors.forename: Ellen
authors.initials: E
authors.lastname: Freed
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.forename: Natalie
authors.initials: N
authors.lastname: Vena
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Milan G
authors.initials: MG
authors.lastname: Chheda
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.forename: Yashaswi
authors.initials: Y
authors.lastname: Shrestha
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Boehm
authors.forename: Supriya
authors.initials: S
authors.lastname: Jain
authors.forename: Emeric
authors.initials: E
authors.lastname: Bojarski
authors.forename: Craig
authors.initials: C
authors.lastname: Mermel
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Charles S
authors.initials: CS
authors.lastname: Fuchs
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: 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*
chemical_list: D015513:Oncogene Proteins; D051176:beta Catenin; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases
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