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

Anne Serrao1, Laura M Jenkins1, Alexander A Chumanevich2

  • 1Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.

Oncogene
|May 22, 2018
PubMed

Insights

Cyclin-dependent kinase 8 (CDK8) and CDK19 inhibition block cancer cell invasion by disrupting the SMAD1-driven epithelial-to-mesenchymal transition (EMT) pathway, highlighting CDK8 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cyclin-dependent kinase 8 (CDK8) regulates transcription and is implicated in cancer.
  • The interplay between CDK8, YAP1, and SMAD1 in cancer-related epithelial-to-mesenchymal transition (EMT) is not fully understood.

Purpose of the Study:

  • To investigate the role of the CDK8/YAP1 pathway in SMAD1-driven EMT and cancer invasion.
  • To determine the therapeutic potential of targeting CDK8/19 in cancer.

Main Methods:

  • Utilized various cancer models, including in vitro and in vivo murine syngeneic models.
  • Employed genetic and pharmacological inhibition of CDK8 and CDK19.
  • Performed RNA-sequencing meta-analysis.

Main Results:

  • SMAD1-driven EMT is dependent on matrix rigidity and YAP1.
  • Inhibition of CDK8/19 abrogates BMP-induced EMT, tumor cell invasion, and EMT-associated transcription factor changes.
  • CDK8 inhibition reduces YAP nuclear localization and E-cadherin expression.
  • A correlation exists between CDK8 expression and EMT transcription factors in patients.

Conclusions:

  • CDK8 coordinates growth factor and mechanical signals during EMT and invasion.
  • Targeting CDK8/19 presents a promising therapeutic strategy for inhibiting cancer cell invasion.

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