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Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XIV | Pages 60 - 60
1 Apr 2012
Wolahan B D'Arcy P Maruwge W Brodin B
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SSX was initially identified as a melanoma associated tumour antigen MEL2 and in the SS18/SSX fusion gene of synovial sarcoma. It consists of a family of nine, highly homologous X chromosome genes, being SSX1, SSX2 and SSX4 the most commonly expressed in tumours. In normal tissue, SSX expression is restricted to germ cells, trophoblasts, and mesenchymal stem cells. In malignant cells, SSX expression is over-represented in sarcomas. SSX expression is epigenetically regulated by methylation and histone deacetylation.

Aim

To investigate the oncogenic properties of SSX. Validate it as tumour target and identify lead compounds.

Methods

RNAi system for conditional silencing of SSX expression, Protein analysis and Mass Spec, PCR arrays, tumour xenographs and drug library screening.


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 460 - 461
1 Jul 2010
Darcy P Maruwge W Brodin B
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Mutations of the p53 gene are uncommon in synovial sarcoma, a high-grade tumor genetically characterized by the chromosomal translocation t:(X;18), that results in the fusion of SS18 with SSX gene.

We recently reported that SS18-SSX1 negatively regulates the stability of p53 by promoting its ubiquitination and degradation in a manner dependent on the ubiquitin ligase activity of HDM2. The negative effect of SS18-SSX1 expression on p53 was mediated by its ability to promote HDM2 stabilization through inhibition of HDM2 autoubiquitination. The final outcome translates into a deficient transactivation of p53-regulated genes: HDM2, PUMA, and NOXA that are important to preserve genomic integrity in response to cellular stress.

Our data uncovers a novel mechanism whereby, in synovial sarcoma cells with wild

type p53, the SS18-SSX oncoprotein can negatively regulate p53 tumor-suppressive function by increasing the stability of its negative regulator HDM2.

We further hypothesise that chemical compounds that target the p53-HDM2 regulatory axis may rescue p53 function in synovial sarcoma. With this in mind we investigated the potential of the HDM2 antagonists, nutlin-3 and of the recently discovered tenovin 1, to rescue p53 activity in synovial sarcoma cells lines. Nutlin-3 effectively stabilized p53 half-life and trans-activating function, resulting in cell growth arrest and apoptosis.

We further observed that chemotherapeutic agents like doxorubicin also stabilized p53 in response to DNA damage but did not restore p53 transcriptional activity due to rapid complexing of p53 to HDM2. On the contrary, nutlin-,3 stabilized p53 and inhibited p53-HDM2 interaction, thereby rescuing p53 tumor suppression function. Our results suggest that the inhibition of the p53-HDM2 interaction by small molecules is a highly potential therapeutic strategy for soft tissue sarcomas with wild type p53.