title: Cdk8 deletion in the Apc(Min) murine tumour model represses EZH2 activity and accelerates tumourigenesis.
abstract: CDK8 is a dissociable kinase module of the Mediator complex and has been shown to play an important role in transcriptional regulation in organisms as diverse as yeast and humans. Recent studies suggest that CDK8 functions as an oncoprotein in melanoma and colon cancer. Importantly, these studies were conducted using in vitro cell line models and the role of CDK8 in tumourigenesis in vivo has not been explored. We have generated a mouse with a Cdk8 conditional knockout allele and examined the consequences of Cdk8 loss on normal tissue homeostasis and tumour development in vivo. Cdk8 deletion in the young adult mouse did not induce any gross or histopathological abnormalities, implying that Cdk8 is largely dispensable for somatic cellular homeostasis. In contrast, Cdk8 deletion in the Apc(Min) intestinal tumour model shortened the animals' survival and increased tumour burden. Although Cdk8 deletion did not affect tumour initiation, intestinal tumour size and growth rate were significantly increased in Cdk8-null animals. Transcriptome analysis performed on Cdk8-null intestinal cells revealed up-regulation of genes that are governed by the Polycomb group (PcG) complex. In support of these findings, Cdk8-null intestinal cells and tumours displayed a reduction in histone H3K27 trimethylation, both globally and at the promoters of a number of PcG-regulated genes involved in oncogenic signalling. Together, our findings uncover a tumour suppressor function for CDK8 in vivo and suggest that the role of CDK8 activity in driving oncogenesis is context-specific. Sequencing data were deposited at GEO (Accession No. GSE71385).
authors.affiliation: Department of Pathology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: McCleland
authors.affiliation: Department of Molecular Biology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Soukup
authors.affiliation: Department of Pathology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Scot D
authors.initials: SD
authors.lastname: Liu
authors.affiliation: Department of Pathology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Esensten
authors.affiliation: Department of Molecular Biology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: de Sousa e Melo
authors.affiliation: Department of Pathology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Yaylaoglu
authors.affiliation: Department of Molecular Biology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Soren
authors.initials: S
authors.lastname: Warming
authors.affiliation: Department of Molecular Biology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Merone
authors.initials: M
authors.lastname: Roose-Girma
authors.affiliation: Department of Pathology, Genentech Inc, South San Francisco, CA, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D056850:Cyclin-Dependent Kinase 8 / Q000235:genetics*; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D016133:Polymerase Chain Reaction
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; C524803:Cdk8 protein, mouse; D056850:Cyclin-Dependent Kinase 8
keywords: ApcMin; Cdk8; colon cancer; cyclin C