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Updated: Oct 15, 2025
Evaluation of Biomarkers in Glioma by Immunohistochemistry on Paraffin-Embedded 3D Glioma Neurosphere Cultures
Published on: January 9, 2019
Heterogeneity of subsets in glioblastoma mediated by Smad3 palmitoylation
Xiaoqing Fan1,2,3, Junqi Fan1,2, Haoran Yang1,3,4
1Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, No. 350, Shushan Hu Road, Hefei, Anhui 230031, China. MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, University of Science & Technology of China, No. 96, Jin Zhai Road, Hefei, Anhui, 230027, China.
Abstract:
Glioblastoma (GBM) is the most common and deadly of the primary intracranial tumors and is comprised of subsets that show plasticity and marked heterogeneity, contributing to the lack of success in genomic profiling to guide development of precision medicine for these tumors. In this study, a mutation in isocitrate dehydrogenase 1 was found to suppress the transforming growth factor-beta signaling pathway and E2F4 interacted with Smad3 to inhibit expression of mesenchymal markers. However, palmitoylation of Smad3 mediated by palmitoyltransferase ZDHHC19 promoted activation of the transforming growth factor-beta signaling pathway, and its interaction with EP300 promoted expression of mesenchymal markers in the mesenchymal subtype of GBM. Smad3 and hypoxia-inducible factor 1-alpha may be important molecular targets for treatment of glioma because they appear to coordinate the basic aspects of cancer stem cell biology.
Insights
Glioblastoma stem cells exhibit plasticity. Transforming growth factor-beta signaling pathway activation, influenced by Smad3 and palmitoylation, promotes mesenchymal markers in glioblastoma, suggesting new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- Glioblastoma (GBM) is a highly aggressive primary brain tumor characterized by significant cellular heterogeneity and plasticity.
- Current genomic profiling approaches have limited success in guiding precision medicine for GBM due to its complex nature.
Purpose of the Study:
- To investigate the molecular mechanisms regulating glioblastoma heterogeneity and identify potential therapeutic targets.
- To elucidate the role of transforming growth factor-beta signaling and Smad3 in GBM pathogenesis.
Main Methods:
- Analysis of isocitrate dehydrogenase 1 (IDH1) mutations and their effect on transforming growth factor-beta (TGF-β) signaling.
- Investigating the interaction between E2F4 and Smad3 in regulating mesenchymal markers.
- Examining the role of Smad3 palmitoylation by ZDHHC19 and its interaction with EP300 in GBM subtypes.
Main Results:
- IDH1 mutations were found to suppress the TGF-β signaling pathway.
- E2F4 interaction with Smad3 inhibited the expression of mesenchymal markers.
- Palmitoylation of Smad3 by ZDHHC19 activated TGF-β signaling and promoted mesenchymal marker expression in mesenchymal GBM.
- Smad3 and hypoxia-inducible factor 1-alpha (HIF-1α) were identified as key regulators of cancer stem cell biology.
Conclusions:
- The study reveals distinct roles of Smad3 in GBM, with its activity modulated by IDH1 mutations and palmitoylation.
- Targeting Smad3 and HIF-1α may offer novel therapeutic strategies for glioblastoma, particularly for addressing cancer stem cell properties.
