TY - JOUR
T1 - Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer
AU - Serrao, Anne
AU - Jenkins, Laura M.
AU - Chumanevich, Alexander A.
AU - Horst, Ben
AU - Liang, Jiaxin
AU - Gatza, Michael L.
AU - Lee, Nam Y.
AU - Roninson, Igor B.
AU - Broude, Eugenia V.
AU - Mythreye, Karthikeyan
N1 - Funding Information:
Acknowledgements 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.).
Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.
PY - 2018/8/30
Y1 - 2018/8/30
N2 - 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.
AB - 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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U2 - 10.1038/s41388-018-0316-y
DO - 10.1038/s41388-018-0316-y
M3 - Article
C2 - 29780169
AN - SCOPUS:85047158801
VL - 37
SP - 4792
EP - 4808
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 35
ER -