Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis

Mark L. McCleland, Tim M. Soukup, Scot D. Liu, Jonathan H. Esensten, Felipe De Sousa E Melo, Murat Yaylaoglu, Soren Warming, Merone Roose-Girma, Ron Firestein

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

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 ApcMin 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).

Original languageEnglish
Pages (from-to)508-519
Number of pages12
JournalJournal of Pathology
Volume237
Issue number4
DOIs
Publication statusPublished - 1 Dec 2015

Keywords

  • Apc
  • Cdk8
  • colon cancer
  • cyclin C

Cite this

McCleland, M. L., Soukup, T. M., Liu, S. D., Esensten, J. H., De Sousa E Melo, F., Yaylaoglu, M., ... Firestein, R. (2015). Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis. Journal of Pathology, 237(4), 508-519. https://doi.org/10.1002/path.4596
McCleland, Mark L. ; Soukup, Tim M. ; Liu, Scot D. ; Esensten, Jonathan H. ; De Sousa E Melo, Felipe ; Yaylaoglu, Murat ; Warming, Soren ; Roose-Girma, Merone ; Firestein, Ron. / Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis. In: Journal of Pathology. 2015 ; Vol. 237, No. 4. pp. 508-519.
@article{7d531509bbc6432caae8f00303d58c3b,
title = "Cdk8 deletion in the ApcMin 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 ApcMin 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).",
keywords = "Apc, Cdk8, colon cancer, cyclin C",
author = "McCleland, {Mark L.} and Soukup, {Tim M.} and Liu, {Scot D.} and Esensten, {Jonathan H.} and {De Sousa E Melo}, Felipe and Murat Yaylaoglu and Soren Warming and Merone Roose-Girma and Ron Firestein",
year = "2015",
month = "12",
day = "1",
doi = "10.1002/path.4596",
language = "English",
volume = "237",
pages = "508--519",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "Wiley-Blackwell",
number = "4",

}

McCleland, ML, Soukup, TM, Liu, SD, Esensten, JH, De Sousa E Melo, F, Yaylaoglu, M, Warming, S, Roose-Girma, M & Firestein, R 2015, 'Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis', Journal of Pathology, vol. 237, no. 4, pp. 508-519. https://doi.org/10.1002/path.4596

Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis. / McCleland, Mark L.; Soukup, Tim M.; Liu, Scot D.; Esensten, Jonathan H.; De Sousa E Melo, Felipe; Yaylaoglu, Murat; Warming, Soren; Roose-Girma, Merone; Firestein, Ron.

In: Journal of Pathology, Vol. 237, No. 4, 01.12.2015, p. 508-519.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis

AU - McCleland, Mark L.

AU - Soukup, Tim M.

AU - Liu, Scot D.

AU - Esensten, Jonathan H.

AU - De Sousa E Melo, Felipe

AU - Yaylaoglu, Murat

AU - Warming, Soren

AU - Roose-Girma, Merone

AU - Firestein, Ron

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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 ApcMin 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).

AB - 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 ApcMin 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).

KW - Apc

KW - Cdk8

KW - colon cancer

KW - cyclin C

UR - http://www.scopus.com/inward/record.url?scp=84951180291&partnerID=8YFLogxK

U2 - 10.1002/path.4596

DO - 10.1002/path.4596

M3 - Article

C2 - 26235356

AN - SCOPUS:84951180291

VL - 237

SP - 508

EP - 519

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 4

ER -

McCleland ML, Soukup TM, Liu SD, Esensten JH, De Sousa E Melo F, Yaylaoglu M et al. Cdk8 deletion in the ApcMin murine tumour model represses EZH2 activity and accelerates tumourigenesis. Journal of Pathology. 2015 Dec 1;237(4):508-519. https://doi.org/10.1002/path.4596