Analysis on oncogenic mechanisms and therapeutic targets in Ewing's sarcoma

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The translocation t(11;22)(q24:q12) is a specific chromosomal abnormality detected in Ewing's sarcoma (ES). The translocation results in an EWS-Fli1 fusion gene, made up of the 5' half of the EWS gene on chromosome 22 fused to the 3' half of the Fli1 gene on chromosome 11. Recent studies have evaluated transforming potentials of the fusion gene products acting as an aberrant transcription factor. However, the biological significance of EWS-Fli1 is still unknown. We have reported that G1 cyclins including cyclin D1 and cyclin E were upregulated by EWS-Fli1, whereas CDK inhibitors, p21 and p27, were downregulated. These molecules are located in the upstream of retinoblastoma tumor suppressor gene Rb, therefore EWS-Fli1 might affect Rb pathway in ES leading to oncogenesis of the tumor. On the other hand, the abnormality in p53 pathway has not been well analyzed in ES yet. In the present study, we investigated the effects of EWS-Fli1 on p53 pathway and its function, especially the inductio … More n of apoptosis in ES cells. The immunoprecipitation assay revealed that EWS-Fli1 bound to p53 protein, and inhibited its function in p53 wild type ES cells. However, EWS-Fli1 did not significantly affect the expression of apoptosis-related genes located in the downstream of p53 transcription factor. The expression of p21, one of the target genes of p53, was inhibited by EWS-Fli1 via the suppression of the activity of p21 gene promoter. Therefore, we hypothesized that histone deacetylase inhibitors (HDACI) which are known to induce p21 expression in cancer cells might be effective on ES cells. HDACI inhibited ES cell growth via induction of p21 expression both in vitro and in vivo. However, a certain type of HDACI showed cross-resistance to the drug-resistant ES cells. Thus we should pay great attention to the resistance of ES cells to HDACIs in clinical trials. We also investigated the effects of the knockdown of EWS-Fli1 expression by siRNA on apoptosis induction in ES cells. The challenge of siRNA against EWS-Fli1 to ES cells did not induce apoptosis, but senescence in ES cells. This observation indicate the new function of EWS-Fli1, i.e., EWS-Fli1 might inhibit the induction of senescence in ES cells which might lead to the oncogenesis of ES. These results suggest that inhibition of these functions of EWS-Fli1 might promise the development of the molecular target therapy for the treatment of ES patients. Less