1. Inhibition of cyclin-dependent kinase 7 down-regulates yes-associated protein expression in mesothelioma cells.
- Author
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Miao J, Kyoyama H, Liu L, Chan G, Wang Y, Urisman A, Yang YL, Liu S, Xu Z, Bin H, Li H, Jablons DM, and You L
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Apoptosis, Biomarkers, Tumor genetics, Case-Control Studies, Cell Proliferation, Cyclin-Dependent Kinases genetics, Cyclin-Dependent Kinases metabolism, Down-Regulation, Humans, Mesothelioma genetics, Mesothelioma metabolism, Pleural Neoplasms genetics, Pleural Neoplasms metabolism, Prognosis, Signal Transduction, Transcription Factors genetics, Transcription Factors metabolism, Tumor Cells, Cultured, YAP-Signaling Proteins, Cyclin-Dependent Kinase-Activating Kinase, Adaptor Proteins, Signal Transducing antagonists & inhibitors, Biomarkers, Tumor metabolism, Cyclin-Dependent Kinases antagonists & inhibitors, Gene Expression Regulation, Neoplastic, Mesothelioma pathology, Pleural Neoplasms pathology, Transcription Factors antagonists & inhibitors
- Abstract
Cyclin-dependent kinase 7 (CDK7) is a protein kinase that plays a major role in transcription initiation. Yes-associated protein (YAP) is a main effector of the Hippo/YAP signalling pathway. Here, we investigated the role of CDK7 on YAP regulation in human malignant pleural mesothelioma (MPM). We found that in microarray samples of human MPM tissue, immunohistochemistry staining showed correlation between the expression level of CDK7 and YAP (n = 70, r = .513). In MPM cells, CDK7 expression level was significantly correlated with GTIIC reporter activity (r = .886, P = .019). Inhibition of CDK7 by siRNA decreased the YAP protein level and the GTIIC reporter activity in the MPM cell lines 211H, H290 and H2052. Degradation of the YAP protein was accelerated after CDK7 knockdown in 211H, H290 and H2052 cells. Inhibition of CDK7 reduced tumour cell migration and invasion, as well as tumorsphere formation ability. Restoration of the CDK7 gene rescued the YAP protein level and GTIIC reporter activity after siRNA knockdown in 211H and H2052 cells. Finally, we performed a co-immunoprecipitation analysis using an anti-YAP antibody and captured the CDK7 protein in 211H cells. Our results suggest that CDK7 inhibition reduces the YAP protein level by promoting its degradation and suppresses the migration and invasion of MPM cells. Cyclin-dependent kinase 7 may be a promising therapeutic target for MPM., (2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2020
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