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

Abstract

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.