Abstract
The SS18 and SSX genes were initially identified based on their
reoccurrence as fusion partners in synovial sarcoma. As a result of the
specific chromosomal translocation t(X:18), the SS18 gene from chromosome
18 becomes fused with members of the SSX gene family on the X chromosome
resulting in the generation of a novel chimeric fusion gene SS18-SSX. The
SS18 gene encodes a ubiquitously expressed transcriptional activator,
whereas the SSX gene encodes a transcriptional repressor whose expression
is restricted to germ cells and numerous cancers. Thus, the resultant
SS18-SSX fusion gene encodes a transcription factor with dual trans
activation and repression properties; the expression of which is the
initiating event of synovial sarcoma.
We present the findings that SSX, along with several other members of the
CT-antigen family is expressed in mesenchymal stem cells and their
expression is down regulated following differentiation. Knockdown of SSX
could effectively impair cell migration, a phenotype associated with down
regulation of MMP2 expression adding a functional role for SSX in stem
and tumor cell migration. We further explored the potential oncogenic
mechanism of SSX expression by investigating the in vitro and in vivo
role of SSX in altering cell growth and cell cycle progression. Using an
inducible siRNA system we show that knockdown of endogenously expressed
SSX can inhibit cell proliferation and tumor growth of in vivo
xenographs. We demonstrate that SS18-SSX induces p53 ubiquitination,
degradation and prevents the transactivation of p53 target genes
following the induction of a stress response. The negative effect on p53
function was attributed to the ability of SS18-SSX to stabilize HDM2. We
developed this notion by studying the p53 pathway in synovial sarcoma
cell lines expressing wild type p53. We show that these cells were
defective for inducing p53 trans activation in response to genotoxic
stress; however treatment with the HDM2 antagonist nutlin-3A can could
effectively restore p53 trans activation and apoptosis, suggesting that
targeting the p53- HDM2 auto regulatory loop may be of therapeutic
benefit for synovial sarcoma.
