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SYT-SSX Is Critical for Cyclin D1 Expression in Synovial Sarcoma Cells

A Gain of Function of the t(X;18)(p11.2;q11.2) Translocation¹

Departments of Oncology and Pathology [Y. X., K. H., A. B., B. B., O. L.] and Orthopedics [G. N.], Karolinska Hospital, SE-171 76 Stockholm, Sweden; Department of Orthopedics, Stockholm Soder Hospital, SE-118 83 Stockholm, Sweden [B. S.]; Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden [N. M.]; Department of Immunology, Regina Elena Cancer Institute, 00158 Rome, Italy [A. G.]; Department of Oncology, Zhongnan Hospital, Wuhan University, 430071 Wuhan, People’s Republic of China [Y. X.]; and Department of Biological Science, Dublin Institute of Technology, Dublin 2, Ireland [K. H.]

The SYT-SSX fusion gene has been implicated in the malignant tumor cell growth of synovial sarcoma, but the underlying molecular mechanisms are still poorly understood. Here we demonstrate that SYT-SSX is critical for the protein level of cyclin D1 in synovial sarcoma cells. Antisense oligonucleotides to SYT-SSX mRNA rapidly and drastically decreased cyclin D1 and subsequently inhibited cell growth. This effect is specific for SYT-SSX, without involving the wild-type genes SYT or SSX. The decrease in cyclin D1 expression, which occurred shortly after inhibition of SYT-SSX expression, was found to be primarily dependent on an increased degradation of the cyclin D1 protein, as assessed by pulse-chase experiments using [³⁵S]methionine. Furthermore, transfection of mouse fibroblasts with SYT-SSX cDNA increased the stability of cyclin D1. Because treatment with a proteasome inhibitor restored cyclin D1 expression, it seems like SYT-SSX interferes with ubiquitin-dependent degradation of cyclin D1. However, SYT-SSX-regulated cyclin D1 expression was proven to be independent of the glycogen synthetase kinase-3ß pathway. Taken together, our study provides evidence that SYT-SSX stabilizes cyclin D1 and is critical for cyclin D1 expression in synovial sarcoma cells. SYT-SSX-dependent expression of cyclin D1 may be an important mechanism in the development and progression of synovial sarcoma and also raises the possibility for targeted therapy.

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