Published April 19, 2022 | Version v1
Journal article Open

High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML

Authors/Creators

  • 1. Group of Cellular Oncology, Biodonostia Health Research Institute, 20014 San Sebastian, Spain
  • 2. CIC bioGUNE, Derio, Spain
  • 3. Donostia University Hospital, 20014 San Sebastian, Spain
  • 4. Centre for Regenerative Medicine & Edinburgh Cancer Research UK Centre, Institute for Regeneration and Repair, Edinburgh EH16 4UU, UK
  • 5. Group of Molecular Oncology, Biodonostia Health Research Institute, 20014 San Sebastian, Spain
  • 6. Institute of Pathology, University Hospital Basel, 48009 Basel, Switzerland
  • 7. The Francis Crick Institute, London NW1 1AT, UK

Description

Glioma stem cells (GSCs) are critical targets for glioma therapy. SOX9 is a transcription factor with critical roles during neurodevelopment, particularly within neural stem cells. Previous studies showed that high levels of SOX9 are associated with poor glioma patient survival. SOX9 knockdown impairs GSCs proliferation, confirming its potential as a target for glioma therapy. In this study, we characterized the function of SOX9 directly in patient-derived glioma stem cells. Notably, transcriptome analysis of GSCs with SOX9 knockdown revealed STAT3 and PML as downstream targets. Functional studies demonstrated that SOX9, STAT3, and PML form a regulatory loop that is key for GSC activity and self-renewal. Analysis of glioma clinical biopsies confirmed a positive correlation between SOX9/STAT3/PML and poor patient survival among the cases with the highest SOX9 expression levels. Importantly, direct STAT3 or PML inhibitors reduced the expression of SOX9, STAT3, and PML proteins, which significantly reduced GSCs tumorigenicity. In summary, our study reveals a novel role for SOX9 upstream of STAT3, as a GSC pathway regulator, and presents pharmacological inhibitors of the signaling cascade. 

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