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

Academic Article

Abstract

  • © 2018, Macmillan Publishers Limited, part of Springer Nature. 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.
  • Digital Object Identifier (doi)

    Author List

  • Serrao A; Jenkins LM; Chumanevich AA; Horst B; Liang J; Gatza ML; Lee NY; Roninson IB; Broude EV; Mythreye K
  • Start Page

  • 4792
  • End Page

  • 4808
  • Volume

  • 37
  • Issue

  • 35