Inhibition of CDK7-dependent transcriptional addiction is a potential therapeutic target in synovial sarcoma.

Autor: Li X; Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: lixiaoyangniuniu@hotmail.com., Dean DC; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA; Department of Orthopaedic Surgery, Keck School of Medicine at University of Southern California (USC), USC Norris Comprehensive Cancer Center, 1441 Eastlake Ave, NTT 3449, Los Angeles, California, 90033, USA. Electronic address: dylan.dean@med.usc.edu., Yuan J; Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address: yuanxiaojim@outlook.com., Temple TH; Sarcoma Biology Laboratory, Department of Orthopaedics, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, Florida 33136, USA. Electronic address: HTemple@med.miami.edu., Trent JC; Department of Medicine, Hematology & Oncology, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, Florida 33136, USA. Electronic address: JTrent@med.miami.edu., Rosenberg AE; Departments of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, Florida 33136, USA. Electronic address: ARosenberg@med.miami.edu., Yu S; Department of Orthopedics, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address: shengjiyu@126.com., Hornicek FJ; Sarcoma Biology Laboratory, Department of Orthopaedics, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, Florida 33136, USA; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: fjh21@med.miami.edu., Duan Z; Sarcoma Biology Laboratory, Department of Orthopaedics, Sylvester Comprehensive Cancer Center, and the University of Miami Miller School of Medicine, Miami, Florida 33136, USA; Sarcoma Biology Laboratory, Department of Orthopaedic Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: zxd221@med.miami.edu.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2022 May; Vol. 149, pp. 112888. Date of Electronic Publication: 2022 Mar 31.
DOI: 10.1016/j.biopha.2022.112888
Abstrakt: Synovial sarcoma is typical aggressive malignant without satisfactory treatment outcome in adult series. Cyclin-dependent kinases (CDKs) in transcription have been considered promising molecular targets in cancer. Among these, CDK7 has been shown to play important roles in the pathogenesis of malignancies. However, the modulation mechanism of CDK7-regulated transcription in synovial sarcoma is unknown. In the present study, we aim to determine the expression and function of CDK7 in the transcription cycle of RNA polymerase II (RNAP II), and evaluate its prognostic and therapeutic significance in synovial sarcoma. Results showed that overexpression of CDK7 correlates with higher clinical stage and grade, and worse outcomes in clinic. High CDK7 expression was confirmed in all tested human synovial sarcoma cell lines and CDK7 was largely localized to the cell nucleus. Downregulation through siRNA or inhibition with the CDK7-targeting agent BS-181 exhibited dose-dependent cytotoxicity and prevented cell colony formation. Western blots demonstrated that inhibition of CDK7 paused transcription by a reduction of RNAP II phosphorylation. Blocking CDK7-dependent transcriptional addiction was accompanied by promotion of apoptosis. Furthermore, the CDK7-specific inhibitor reduced 3D spheroid formation and migration of synovial sarcoma. Collectively, our findings highlight the role of CDK7-dependent transcriptional addiction in human synovial sarcoma. CDK7-specific cytotoxic agents are therefore promising novel treatment options for synovial sarcoma.
(Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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