Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer.
Mediator kinase CDK8/CDK19 drives YAP1-dependent BMP4-induced EMT in cancer.
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DOI：
10.1038/s41388-018-0316-y
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发表时间：
2018-08
期刊：
影响因子：
8
通讯作者：
Mythreye K
中科院分区：
文献类型：
--
作者：
Serrao A;Jenkins LM;Chumanevich AA;Horst B;Liang J;Gatza ML;Lee NY;Roninson IB;Broude EV;Mythreye K
CDK 8是一种转录调节激酶，通过YAP 1募集控制TGF-β/BMP-应答性SMAD转录激活和周转。然而，CDK 8/YAP 1通路如何影响癌症中的SMAD 1反应仍不清楚。在这里，我们报告说，SMAD 1驱动的上皮间质转化（EMT）是严重依赖于基质刚性和YAP 1在广泛的癌症模型。我们发现，遗传和药理学抑制CDK 8和它的同源孪生激酶CDK 19导致废除BMP诱导的EMT。值得注意的是，在鼠同基因EMT模型中，选择性阻断CDK 8/19在体外和体内特异性地消除肿瘤细胞侵袭、EMT相关转录因子、E-钙粘蛋白表达和雅普核定位的变化。此外，RNA-seq荟萃分析揭示了患者中CDK 8和EMT相关转录因子之间的直接相关性。我们的研究结果表明，CDK 8，一个新兴的治疗靶点，协调生长因子和机械线索在EMT和入侵。
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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影响因子：
16.8
作者：
通讯作者：
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影响因子：
3.3
作者：
Leight JL;Wozniak MA;Chen S;Lynch ML;Chen CS
通讯作者：
Chen CS
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J
影响因子：
64.5
作者：
Hoadley KA;Yau C;Wolf DM;Cherniack AD;Tamborero D;Ng S;Leiserson MDM;Niu B;McLellan MD;Uzunangelov V;Zhang J;Kandoth C;Akbani R;Shen H;Omberg L;Chu A;Margolin AA;Van't Veer LJ;Lopez-Bigas N;Laird PW;Raphael BJ;Ding L;Robertson AG;Byers LA;Mills GB;Weinstein JN;Van Waes C;Chen Z;Collisson EA;Cancer Genome Atlas Research Network;Benz CC;Perou CM;Stuart JM
通讯作者：
Stuart JM
DOI：
10.1051/bmdcn/2017070101
发表时间：
2017-03
期刊：
BioMedicine
影响因子：
--
作者：
Liu YL;Liu JH;Wang IK;Ju SW;Yu TM;Chen IR;Liu YC;Huang CM;Lin SY;Chang CT;Huang CC
通讯作者：
Huang CC