Impairment of p53 acetylation by EWS-Fli1 chimeric protein in Ewing family tumors.
The chromosomal translocation t(11;22)(q24;q12) yields the EWS-Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs). Previous studies have shown the ability of EWS-Fli1 chimeric protein to silence p53 activity. Here we demonstrate that the introduction of EWS-Fli1 significantly inhibited p300-mediated acetylation of p53 at Lys-382 and ... depletion of EWS-Fli1 protein by small interfering RNAs (siRNA) in EFTs cells facilitated it in response to DNA damage. Furthermore, the deacetylation of p53 by EWS-Fli1 suppressed its transcriptional activity and enhanced mdm2-mediated p53 degradation. On the other hand, immunoprecipitation study shows that N-terminal region of EWS-Fli1 associated with histone deacetylase 1 (HDAC1) to forms a complex with p53. Knockdown of HDAC1, but not HDAC2 or HDAC3 protein restored the expression of p53 Lys-382 in EFTs cells. Overexpression of HDAC1 also significantly inhibited p53 transcriptional activity. Pharmacologic inhibitor of HDAC, trichostatin A (TSA) promoted p53-p300 interaction and recruitment of p53 Lys-382 to promoter regions of its target genes p21 and Puma, consequently inducing apoptosis and stabilizing the acetylation of p53 at Lys-382 together with the upregulation of p21 and Puma, which were impaired in EFTs cells after the knockdown of p53 expression. Our data indicate EWS-Fli1 might deacetylate p53 to inhibit its transcriptional function and protein stability via the recruitment of HDAC1. These results might elucidate a novel molecular mechanism about the abrogation of p53 pathway by EWS-Fli1 in EFTs pathogenesis.
Mesh Terms:
Acetylation, Animals, Apoptosis, Bone Neoplasms, Cell Line, Tumor, E1A-Associated p300 Protein, Histone Deacetylase 1, Humans, Hydroxamic Acids, Mice, NIH 3T3 Cells, Oncogene Proteins, Fusion, Proto-Oncogene Protein c-fli-1, Proto-Oncogene Proteins c-mdm2, RNA-Binding Protein EWS, Sarcoma, Ewing, Transcriptional Activation, Tumor Suppressor Protein p53
Acetylation, Animals, Apoptosis, Bone Neoplasms, Cell Line, Tumor, E1A-Associated p300 Protein, Histone Deacetylase 1, Humans, Hydroxamic Acids, Mice, NIH 3T3 Cells, Oncogene Proteins, Fusion, Proto-Oncogene Protein c-fli-1, Proto-Oncogene Proteins c-mdm2, RNA-Binding Protein EWS, Sarcoma, Ewing, Transcriptional Activation, Tumor Suppressor Protein p53
Cancer Lett.
Date: Jul. 01, 2012
PubMed ID: 22266186
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