The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHRpositive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma (Cao et al., 2010). Some of our current studies are aim to understand the transcription regulation of PAX3 and PAX3-FKHR expression via the analysis of their epigenomic modification. Also, PAX3-FKHR up-regulates a HDAC gene which we have showed to be essential for the survival of rhabdomyosarcoma cells. We are exploring the possibility of using this information for the preclinical evaluation of HDAC inhibitors against the tumor and the identification of biomarkers predictive of response to this class of agents. We have established that HDAC5 is a down-stream target and a potential drug target. We are the process of preparing a manuscript.
| Cao, Liang; Yu, Yunkai; Bilke, Sven et al. (2010) Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer. Cancer Res 70:6497-508 |
