| Title: |
High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML |
| Authors: |
Aldaz Donamaría, Paula; Martín Martín, Natalia; Sáenz Antoñanzas, Ander; Carrasco García, Estefanía; Álvarez-Satta, María; Elúa Pinin, Alejandro; Pollard, Steven M.; Lawrie, Charles H.; Moreno-Valladares, Manuel; Samprón Lebed, Nicolás; Hench, Jürgen; Lovell-Badge, Robin; Carracedo Pérez, Arkaitz; Matheu Fernández, Ander |
| Publisher Information: |
MDPI |
| Publication Year: |
2022 |
| Collection: |
ADDI: Repositorio Institucional de la Universidad del País Vasco / Euskal Herriko Unibertsitatea (UPV/EHU - Basque Country University) |
| Subject Terms: |
glioblastoma; glioma stem cell; SOX9; therapy; transcriptome; STAT3; PML; pharmacological inhibition; central-nervous-system; inhibitor STX-0119; temozolomide; expression; growth; stratification; classification; proliferation; tumors |
| 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. ; P.A. and A.S.-A. were recipients of predoctoral fellowships from the AECC foundation and Carlos III Institute (ISCIII), respectively. M.a.-S. holds a Sara Borrell postdoctoral contract from the ISCIII (CD19/00154). E.C.-G. was a recipient of a Stop Fuga de Cerebros postdoctoral fellowship and holds a Miguel Servet contract from the ISCIII (CP19/00085). We thank the Histology Platform of the Biodonostia Health Research Institute, The Neuro-Oncology Committee of Donostia University Hospital, and Basque Biobank for their help. This research was supported by grants from ISCIII and FEDER Funds (CP16/00039, DTS16/00184, PI16/01580, DTS18/00181, PI18/01612, CP19/00085), and the Industry and Health Departments of the Basque Country. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.mdpi.com/1422-0067/23/9/4511/htm; International Journal of Molecular Sciences 23(9) : (2022) // Article ID 4511; https://hdl.handle.net/10810/57790 |
| DOI: |
10.3390/ijms23094511 |
| Availability: |
https://hdl.handle.net/10810/57790; https://doi.org/10.3390/ijms23094511 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/3.0/es/ ; © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). ; Atribución 3.0 España |
| Accession Number: |
edsbas.B1F0FC43 |
| Database: |
BASE |