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GNAO1 overexpression promotes neural differentiation of glioma stem-like cells and reduces tumorigenicity through TRIM21/CREB/HES1 axis

Oncogene volume 44, pages 450–461 (2025)Cite this article

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Abstract

Inducing tumor cell differentiation is a promising strategy for treating malignant cancers, including glioma, yet the critical regulator(s) underlying glioma cell differentiation is poorly understood. Here, we identify G Protein Subunit Alpha O1 (GNAO1) as a critical regulator of neural differentiation of glioma stem-like cells (GSCs). GNAO1 expression was lower in gliomas than in normal neuronal tissues and high expression of GNAO1 correlated with a better prognosis. GNAO1 overexpression markedly promoted neural differentiation of GSCs, leading to decreased cell proliferation and colony formation. Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination. This ubiquitination resulted in the degradation of CREB and further reduced p300-mediated H3K27ac levels of the HES1 promoter. As a result, GNAO1 overexpression downregulated HES1 expression, which reinforced neuronal differentiation. In addition, knockdown of METTL3, a key writer of the N6-methyladenosine (m6A), enhanced GNAO1 mRNA stability. Treatment with GNAO1 adenovirus increased neuronal differentiation of tumor cells and reduced tumor cell proliferation in orthotopic GSC xenografts and temozolomide further enhanced GNAO1 adenovirus effects, resulting in extended animal survival. Our study presents that engineering GNAO1 overexpression-inducing neural differentiation of GSCs is a potential therapy strategy via synergistic inhibition of malignant proliferation and chemotherapy resistance.

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Fig. 1: GNAO1 is a new prognostic factor of glioma.
Fig. 2: GNAO1 overexpression promotes GSC differentiation.
Fig. 3: GNAO1 overexpression enhances GSC differentiation by downregulating neural progenitor gene HES1.
Fig. 4: GNAO1 overexpression decreases CREB protein expression and thereby reduces p300-mediated H3K27 acetylation and HES1 transcription.
Fig. 5: GNAO1 recruits TRIM21 and mediates CREB ubiquitination and degradation.
Fig. 6: METTL3 regulates GNAO1 mRNA stability.
Fig. 7: GNAO1 adenovirus treatment promotes xenograft glioblastoma cell differentiation.

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Data availability

RNA-Seq data reported in this study have been deposited with the Gene Expression Omnibus under the accession GEO ID: GSE234341. (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE234341). The data supporting the findings of this study are available within the article and its Supporting Information files or available from the corresponding author upon reasonable request.

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Funding

This work was supported in part by the National Natural Science Foundation of China (32371004, 82072896 to HF, 32271007 to YL, 82103657 to BS, 82173356 to RY); Program of Shanghai Academic/Technology Research Leader (21XD1403100) to HF; Shanghai Natural Science Foundation (23ZR1441000 to YL).

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Author notes

  1. These authors contributed equally: Bowen Sun, Ge Wang.

Authors and Affiliations

  1. State Key Laboratory of Systems Medicine for Cancer, Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Bowen Sun, Ge Wang, Guoyu Chen, Yingwen Zhang, Ru Yang & Haizhong Feng

  2. Department of Neurosurgery, Third Affiliated Hospital, Naval Medical University, Shanghai, 200438, China

    He Hua

  3. Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China

    Yanxin Li

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Contributions

HF, YL and HH designed and supervised the project. BS, GW, GC and YZ performed experiments. BS and HF interpreted and/or reviewed the data and wrote the manuscript. GW, GC, YZ and RY edited the manuscript. All authors contributed to the article and approved the final manuscript.

Corresponding authors

Correspondence to Ru Yang, He Hua, Yanxin Li or Haizhong Feng.

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Ethics approval and consent to participate

All clinical brain tissue specimens were collected at Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine in accordance with a protocol approved by Shanghai Jiao Tong University Institutional Clinical Care and Use Committee of Renji Hospital (Shanghai, China). The investigators obtained informed written consent from the patients. These specimens were examined and diagnosed by pathologists at Ren Ji Hospital. All animal experiments were conducted under the Institutional Animal Care and Use Committee (IACUC)-approved protocols at Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine following NIH and institutional guidelines. The approval number was RJ2022-0828.

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Sun, B., Wang, G., Chen, G. et al. GNAO1 overexpression promotes neural differentiation of glioma stem-like cells and reduces tumorigenicity through TRIM21/CREB/HES1 axis. Oncogene 44, 450–461 (2025). https://doi.org/10.1038/s41388-024-03234-7

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