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

Oncogene
Anne SerraoKarthikeyan Mythreye

Abstract

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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Citations

Jan 5, 2019·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Tatsuya KitaoHiroaki Shirahase
Jul 5, 2019·International Journal of Cancer. Journal International Du Cancer·Finn BeckerAnne Offermann
Aug 6, 2020·International Journal of Molecular Sciences·Finn-Ole PaulsenAnne Offermann
Jun 30, 2019·Pharmaceuticals·Ingeborg MenzlVeronika Sexl
Aug 7, 2019·Cells·Igor B RoninsonEugenia V Broude
Feb 17, 2021·Clinical & Experimental Metastasis·Asha KumariKarthikeyan Mythreye
Dec 2, 2020·European Journal of Medicinal Chemistry·Dan WuXinhua Liu
Jul 28, 2021·Human Pathology·Anne OffermannSven Perner

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Methods Mentioned

BETA
PCR
nuclear translocation
RNAseq
Flow Cytometry
xenografts
xenograft

Software Mentioned

LI
Leica Application Suite
Fiji Image J
MATLAB
- Biosciences

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