PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1

Autor: Beat W. Schäfer, Chiara Giorgi, Maria E. Gierisch, Aleksandar Boro, Laura A. Lopez-Garcia, Felix Niggli, Florian Rechfeld
Přispěvatelé: University of Zurich, Schäfer, Beat W
Rok vydání: 2015
Předmět:
Oncogene Proteins
Fusion
Transcription
Genetic
Sp1 Transcription Factor
610 Medicine & health
Antineoplastic Agents
Bone Neoplasms
Sarcoma
Ewing
Biology
Transfection
Transcription (biology)
Cell Line
Tumor
Gene expression
Transcriptional regulation
Humans
RNA
Messenger
Promoter Regions
Genetic
Transcription factor
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Sp1 transcription factor
Binding Sites
Dose-Response Relationship
Drug
promoter analysis
Proto-Oncogene Protein c-fli-1
fungi
Imidazoles
Promoter
Cell Cycle Checkpoints
3. Good health
Gene Expression Regulation
Neoplastic
PI3K pathway
Oncology
10036 Medical Clinic
FLI1
Cancer research
Quinolines
2730 Oncology
RNA Interference
Phosphatidylinositol 3-Kinase
RNA-Binding Protein EWS
EWS/FLI1
Proto-Oncogene Proteins c-akt
Ewing sarcoma
Protein Binding
Signal Transduction
Research Paper
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: 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.
Databáze: OpenAIRE
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