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

• Published in: Oncogene 2018-08, Vol.37 (35), p.4792-4808
• Main Authors: Serrao, Anne, Jenkins, Laura M., Chumanevich, Alexander A., Horst, Ben, Liang, Jiaxin, Gatza, Michael L., Lee, Nam Y., Roninson, Igor B., Broude, Eugenia V., Mythreye, Karthikeyan
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 13/95; 14/1; 38/22; 45/77; 631/337/572; 631/67/327; 631/80/84/750; 631/80/86/2368; 64/60; 82/29; 82/80; 96/106; 96/63; Adaptor Proteins, Signal Transducing - genetics; Animal models; Animals; Apoptosis; Bone Morphogenetic Protein 4 - genetics; Bone morphogenetic proteins; Cancer; Carcinogenesis; Cell Biology; Cell Cycle Proteins; Cell Line, Tumor; Cyclin-Dependent Kinase 8 - genetics; Cyclin-Dependent Kinases - genetics; DNA binding proteins; E-cadherin; Epithelial-Mesenchymal Transition - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Genetic aspects; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Localization; Medical research; Medicine; Medicine & Public Health; Mesenchyme; Mice; Oncology; Phosphoproteins - genetics; Phosphotransferases; Ribonucleic acid; RNA; Smad protein; Stem cells; Therapeutic applications; Transcription activation; Transcription factors; Transcription Factors - genetics; Transcriptional Activation - genetics; Transforming growth factors; Tumors; Yes-associated protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0316-y

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.