Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer
| Autor: | Eugenia V. Broude, Michael L. Gatza, Jiaxin Liang, Alexander A. Chumanevich, Anne Serrao, Karthikeyan Mythreye, Laura M. Jenkins, Igor B. Roninson, Nam Y. Lee, Ben Horst |
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| Rok vydání: | 2018 |
| Předmět: |
Transcriptional Activation
0301 basic medicine Cancer Research Epithelial-Mesenchymal Transition medicine.medical_treatment Cell Cycle Proteins Bone Morphogenetic Protein 4 SMAD Biology Article Mice 03 medical and health sciences Mediator Cell Line Tumor Genetics medicine Animals Humans Molecular Biology Transcription factor Adaptor Proteins Signal Transducing Regulation of gene expression YAP1 Kinase Growth factor YAP-Signaling Proteins Cyclin-Dependent Kinase 8 Phosphoproteins Cyclin-Dependent Kinases Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology embryonic structures Cyclin-dependent kinase 8 Female Transcription Factors |
| Zdroj: | Oncogene. 37:4792-4808 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-018-0316-y |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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