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

Oncotarget
Chiara GiorgiFelix K Niggli

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 investiga...Continue Reading

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Citations

Jan 19, 2019·Endocrine Reviews·Andrea Mafficini, Aldo Scarpa
Feb 1, 2019·Scientific Reports·Maria E GierischBeat W Schäfer
Nov 13, 2018·Oncotarget·Nachi NamatameShingo Dan
Dec 27, 2017·International Journal of Cancer. Journal International Du Cancer·Weiying LiuHua Tang
Nov 3, 2017·Science Translational Medicine·Anton G HenssenAlex Kentsis
Jan 13, 2018·The Journal of Endocrinology·Andrea Mafficini, Aldo Scarpa
Jan 23, 2021·Journal of Pediatric Hematology/oncology·Amanda N GoldinDonald L Durden

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Methods Mentioned

BETA
ChIP
electrophoretic mobility shift
immunoprecipitation
FCS
PCR
transfection

Software Mentioned

SDS
GraphPad prism
Alibaba
Genome Browser
Flow Jo
Match

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