High SOX9 Maintains Glioma Stem Cell Activity through a Regulatory Loop Involving STAT3 and PML
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2022-05Author
Aldaz Donamaría, Paula
Martín Martín, Natalia
Sáenz Antoñanzas, Ander
Carrasco-Garcia, Estefania
Álvarez-Satta, María
Elúa Pinin, Alejandro
Pollard, Steven M.
Lawrie, Charles H.
Moreno-Valladares, Manuel
Samprón Lebed, Nicolás
Hench, Jürgen
Lovell-Badge, Robin
Matheu Fernández, Ander
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International Journal of Molecular Sciences 23(9) : (2022) // Article ID 4511
Abstract
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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Except where otherwise noted, this item's license is described as © 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/).