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RGS20 reduces glioma stemness and temozolomide resistance by intrinsically inhibiting the WNT/β-catenin signaling

Yang Xie1,2, Qi Li1,2,3, Yecheng Ma1,2

  • 1Department of Biochemistry and Molecular Biology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.

Scientific Reports
|November 29, 2025
PubMed

Insights

Regulator of G protein signaling 20 (RGS20) inhibition boosts glioma stemness and temozolomide resistance by activating WNT/β-catenin signaling, especially in hypoxic niches. This reveals a novel mechanism driving glioma progression and resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • G protein-coupled receptors (GPCRs) are crucial for normal and cancer stem cell stemness.
  • The role of the Regulator of G protein signaling (RGS) family in tumor stem cells, particularly glioma stem cells (GSCs), is not well understood.

Purpose of the Study:

  • To investigate the role of RGS20 in regulating glioma stemness and resistance to temozolomide (TMZ).
  • To elucidate the underlying molecular mechanisms, including the WNT/β-catenin signaling pathway and the influence of hypoxic microenvironments.

Main Methods:

  • Bioinformatics analysis of clinical data to identify RGS20 as a potential regulator.
  • In vitro and in vivo experiments to assess the effects of RGS20 inhibition on GSCs.
  • Analysis of human glioblastoma specimens to correlate RGS20 expression with β-catenin signaling in hypoxic regions.

Main Results:

  • RGS20 inhibition enhanced GSC sphere formation and stem cell markers by activating WNT/β-catenin signaling.
  • RGS20 inhibition promoted tumorigenesis and temozolomide (TMZ) resistance.
  • Low RGS20 expression correlated with enriched β-catenin signaling in hypoxic regions of glioblastoma, supporting GSC maintenance and TMZ resistance.

Conclusions:

  • Low RGS20 expression sustains WNT/β-catenin signaling in ligand-reduced hypoxic niches, driving glioma progression and TMZ resistance.
  • This study uncovers a novel intracellular mechanism contributing to glioma stemness and therapeutic resistance.
  • Targeting the RGS20-WNT/β-catenin axis in hypoxic niches presents a potential therapeutic strategy for glioma.
Keywords:
HypoxiaRGS20StemnessTMZ-resistanceWNT/β-catenin signaling pathway

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