Analysis of transforming mechanism of human synovial sarcoma oncogene SYT-SSX

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Human synovial sarcoma occurs primarily around the joint of extremities and more than 90% of cases have chromosomal translocation t(X;18) resulting the formation of chimeric gene SYT-SSX (synovial sarcoma translocation-synovial sarcoma X break point). As both of SYT and SSX did not share any homology region of known functional proteins, the transforming mechanism of SYT-SSX has not yet been elucidated. In this project, we established rat fibroblast cell line 3Y1 expressing SYT, SSX, and SYT-SSX, and found that SYT-SSX induced anchorage-independent growth and tumor formation in nude mice. In this SYT-SSX expressing cell lines, one of the SWI/SNF type of chromatin remodeling factor hBRM has been shown to bind to SYT-SSX and this association was essential for the transformation of 3Y1 cells. Especially, as the disruption of the binding of SYT-SSX and hBRM by specific peptides composed of 50 amino acids corresponding to hBRM155-206, suppressed the growth of SYT-SSX-3Y1 cells, these peptides could be one of the basic technique for the establishment of gene therapy for synovial sarcoma. We also found that in contrast to 3Y1 cells, SYT-SSX induced growth suppression of human adenocarcinoma cell line SW13. In this cell line, SYT-SSX induced p21WAF1/CIP1 expression confirmed by immunoblotting. The luciferase assay using p21 promoter-regulated construction, SYT-SSX was found to activate p21 promoter by transcription factor Sp1-dependent and p53-independent mechanism. Thus, SYT-SSX has differential effect for cell growth such as growth positive and growth negative mechanism, in different cell lines. We are currently considering the augmentation of growth negative function of SYT-SSX may induce the tumor cell suppression as a specific therapy of synovial sarcoma.