Abstract
Abstract Birt-Hogg-Dubé (BHD) Syndrome, is a dominantly familial cancer syndrome associated with susceptibility to renal cancer carcinoma (RCC) caused by inactivating mutations in the folliculin (FLCN) gene. The precise functions of the FLCN gene product are still under investigation but RCC from BHD patients show loss of the wild type allele consistent with a tumour suppressor gene function. In search for potential synthetic-lethal targets for FLCN using a phosphatase siRNA library screen approach, we found that knockdown of SSH2 serine phosphatase (one of the three members of Slingshot family and actively involved in Actin reorganization) specifically induced caspase 3/7 activity in a dose-dependent manner (up to 6 fold increase, 10nM, 72hrs) in two human cell lines (BHD-origin renal cell carcinoma UOK-257 and thyroid carcinoma FTC-133) with loss of FLCN expression, but not in their folliculin expressing isogenic cell lines. SSH2 siRNA-induced knockdown was verified by real-time PCR (up to 60% reduction in SSH2 transcripts, 10nM siRNA, 48hrs), but SSH1 and SSH3 transcripts were increased up to 3 fold (suggesting a compensatory regulatory mechanism among members of SSH family). Further investigation of the underlining mechanism of caspase induction by SSH2 knockdown in FLCN-null cells exhibited that there was a dose-dependent increase in G1 cell population (up to 20% increase, 20nM SSH2 siRNA, 72hrs). Combination treatment of SSH2 + SSH1 siRNAs, but not SSH2 + SSH3 siRNAs potentiated induction of caspase 3 activity and G1 cell cycle arrest. These data indicate that apoptotic cell death in FLCN-null cells can be triggered by SSH2 knockdown through G1 arrest and provide a tool to develop potential therapeutic agents for BHD patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-259. doi:1538-7445.AM2012-LB-259
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