Format

Send to

Choose Destination
Oncogene. 2018 Aug;37(35):4792-4808. doi: 10.1038/s41388-018-0316-y. Epub 2018 May 21.

Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer.

Author information

1
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
2
Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, USA.
3
Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
4
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
5
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA. mythreye@sc.edu.
6
Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC, USA. mythreye@sc.edu.

Abstract

CDK8 is a transcription-regulating kinase that controls TGF-β/BMP-responsive SMAD transcriptional activation and turnover through YAP1 recruitment. However, how the CDK8/YAP1 pathway influences SMAD1 response in cancer remains unclear. Here we report that SMAD1-driven epithelial-to-mesenchymal transition (EMT) is critically dependent on matrix rigidity and YAP1 in a wide spectrum of cancer models. We find that both genetic and pharmacological inhibition of CDK8 and its homologous twin kinase CDK19 leads to abrogation of BMP-induced EMT. Notably, selectively blocking CDK8/19 specifically abrogates tumor cell invasion, changes in EMT-associated transcription factors, E-cadherin expression and YAP nuclear localization both in vitro and in vivo in a murine syngeneic EMT model. Furthermore, RNA-seq meta-analysis reveals a direct correlation between CDK8 and EMT-associated transcription factors in patients. Our findings demonstrate that CDK8, an emerging therapeutic target, coordinates growth factor and mechanical cues during EMT and invasion.

PMID:
29780169
DOI:
10.1038/s41388-018-0316-y
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center