PEA3 Transcription Factors, Role in Invasion, Proliferation and Radioresistance of Glioblastoma Stem Cells.

The presence of glioblastoma stem cells (GSCs), known for their high invasiveness and resistance to radiation, is one of the reasons for systematic recurrence. It is therefore important to understand the resistance mechanisms of these cells to optimise therapies. We focused on the PEA3 family of transcription factors, ETV1, ETV4 and ETV5, in patient-derived GSCs. We demonstrate that ETV1 is over-expressed in high invasive GSCs. In 3D invasion assays, inhibiting ETV1 expression using specific siRNAs significantly reduces cell invasion. Furthermore, we show a significant correlation between ETV1 and ZEB1, a major driver of invasion. Blocking ETV1 decreases ZEB1 expression in GSCs. The study also demonstrates the essential role of ETV1, ETV4 and ETV5 in the radioresistance of GSCs and their ability to form neurospheres. Using specific siRNAs to inhibit the expression of these transcription factors led to an increased sensitivity of GSCs to radiation and a decrease in both the number and size of neurospheres. These findings suggest that PEA3 transcription factors play a major role in GSCs aggressiveness by regulating invasion, radioresistance and the ability to form neurospheres. Trial Registration: Registry and the Registration N° of the study/trial: 12TETE01, ID-RCB No. 2012-A00585-38, approval Date: May 7, 2012.