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

Anne Serrao, Laura M. Jenkins, Alexander A. Chumanevich, Ben Horst, Jiaxin Liang, Michael L. Gatza, Nam Y. Lee, Igor B. Roninson, Eugenia V. Broude, Karthikeyan Mythreye

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4792-4808
Number of pages17
JournalOncogene
Volume37
Issue number35
DOIs
StatePublished - Aug 30 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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