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.
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We thank the COBRE Functional Genomics Core (USC Center for Targeted Therapeutics) for lentiviral preparations, COBRE Microscopy and Flow cytometry Core (USC Center for Targeted Therapeutics) for assistance with imaging, Qi Zhang, Zach Mack, Nick Lenze, Priyanka Singh, and Pratik Patel for technical assistance. Grant Support: NIH P20GM109091 (E.V.B., K.M., I.B.R.), Marsha Rivkin Foundation (K.M.), Ovarian Cancer Research Fund (K.M.), University of South Carolina startup funds (K.M.), University of South Carolina SPARC Graduate Student Research, and Predoctoral NIH GM122379-01 (L.M.J.).
A.S., L.M.J., A.C., and J.L. B.H conducted experiments, acquired and analyzed data. M.G. conducted the bioinformatics analyses. N.Y.L. provided reagents and analyzed data. E.V.B., I.B.R., and K.M. designed experiments, analyzed data, and wrote the paper.
Conflict of interest
I.B.R. is the founder and president and J.L., M.C., H.K., K.M, and E.V.B. are consultants of Senex Biotechnology, Inc. Other authors declare no conflict of interest.
Equal first co-authorship: Anne Serrao and Laura M. Jenkins.
These authors contributed equally: Alexander A. Chumanevich, Ben Horst, Jiaxin Liang.
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Serrao, A., Jenkins, L.M., Chumanevich, A.A. et al. Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer. Oncogene 37, 4792–4808 (2018) doi:10.1038/s41388-018-0316-y
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