PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1.
Oncotarget
; 6(30): 28895-910, 2015 Oct 06.
Article
em En
| MEDLINE
| ID: mdl-26336820
ABSTRACT
Ewing sarcoma (ES) is the second most frequent bone cancer in childhood and is characterized by the presence of the balanced translocation t(11;22)(q24;q12) in more than 85% of cases, generating a dysregulated transcription factor EWS/FLI1. This fusion protein is an essential oncogenic component of ES development which is necessary for tumor cell maintenance and represents an attractive therapeutic target. To search for modulators of EWS/FLI1 activity we screened a library of 153 targeted compounds and identified inhibitors of the PI3K pathway to directly modulate EWS/FLI1 transcription. Surprisingly, treatment of four different ES cell lines with BEZ235 resulted in down regulation of EWS/FLI1 mRNA and protein by ~50% with subsequent modulation of target gene expression. Analysis of the EWS/FLI1 promoter region (-2239/+67) using various deletion constructs identified two 14 bp minimal elements as being important for EWS/FLI1 transcription. We identified SP1 as modulator of EWS/FLI1 gene expression and demonstrated direct binding to one of these regions in the EWS/FLI1 promoter by EMSA and ChIP experiments. These results provide the first insights on the transcriptional regulation of EWS/FLI1, an area that has not been investigated so far, and offer an additional molecular explanation for the known sensitivity of ES cell lines to PI3K inhibition.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sarcoma de Ewing
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Transcrição Gênica
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Neoplasias Ósseas
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Transdução de Sinais
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Regulação Neoplásica da Expressão Gênica
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Proteínas de Fusão Oncogênica
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Fator de Transcrição Sp1
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Proteína EWS de Ligação a RNA
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Proteínas Proto-Oncogênicas c-akt
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Proteína Proto-Oncogênica c-fli-1
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article