Targeting regulation of cyclin dependent kinase 9 as a novel therapeutic strategy in synovial sarcoma

Synovial sarcomas hold a low genomic complexity, making it distinct from other types of soft-tissue sarcomas. Many studies focused on targeting the SS18-SSX fusion protein, which presents in over 90% of human synovial sarcomas. This protein acts as an oncogenic promoter in the tumorigenesis of synovial sarcomas, making it an ideal therapeutic target. However, to date there have been no effective strategies targeting SS18-SSX for the treatment of synovial sarcomas. Therefore, it is an urgent need to identify alternative therapeutic targets. More recently, CDK9, a protein involved in RNA transcription regulation, has been investigated for its role in the pathogenesis of cancer. However, the expression and function of CDK9 in synovial sarcomas remains to be elucidated. In the present study, we found that CDK9 was to be largely localized to the cell nucleus, and highly expressed in all tested human synovial sarcoma cell lines and over 90% of human sarcoma tissue microarray samples. High-CDK9 expression was associated with a poorer patient prognosis of human sarcomas. Inhibition of CDK9, with either siRNA or a CDK9 inhibitor, prevented synovial sarcoma cell growth and proliferation in a dose-dependent manner. This was also accompanied with a reduction in the phosphorylation of RNA polymerase II and an increase in the expression of anti-apoptotic proteins. Moreover, CDK9 inhibition decreased sarcoma cell spheroid formation and cell motility. Collectively, these findings highlight the importance of CDK9 in human synovial sarcoma cell growth and proliferation. Therefore, CDK9 may represent a promising target for the treatment of synovial sarcomas. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:510-521, 2019.