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

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

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Bone Morphogenetic Protein 4 / genetics*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 8 / genetics*
  • Cyclin-Dependent Kinases / genetics*
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Mice
  • Phosphoproteins / genetics*
  • Transcription Factors / genetics
  • Transcriptional Activation / genetics
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Bmp4 protein, mouse
  • Bone Morphogenetic Protein 4
  • Cell Cycle Proteins
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Cdk8 protein, mouse
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases