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Transcription factor YY1 mediates self-renewal of glioblastoma stem cells through regulation of the SENP1/METTL3/MYC axis

Cancer Gene Therapy volume 30, pages 683–693 (2023)Cite this article

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Abstract

Glioma is a primary brain tumor with limited treatment approaches and glioblastoma stem cells (GSCs) are manifested with the self-renewal capability and high tumorigenic capacity. This study was performed to investigate the regulatory effect of the SUMO-specific protease 1 (SENP1)/methyltransferase-like 3 (METTL3)/MYC axis on the self-renewal of GSCs mediated by transcription factor Yin Yang 1 (YY1). Following bioinformatics analysis and clinical and cellular experiments, we found that YY1 was highly expressed in GBM tissues and cells, while silencing its expression reduced the self-renewal ability of GSCs. Functionally, YY1 promoted the transcriptional expression of SENP1 by binding to the promoter region of SENP1, while the deSUMOase SENP1 facilitated the methylase activity of m6A through deSUMOylation of the methylase METTL3, thereby promoting the m6A modification of MYC mRNA via METL3 and promoting the expression of MYC. A nude mouse xenograft model of GBM was also constructed to examine the tumorigenicity of GSCs. The obtained findings demonstrated that YY1 promoted tumorigenicity of GSCs by promoting the expression of MYC in vivo. Conclusively, YY1 can transcriptionally upregulate the SUMOylase SENP1 and enhance the methylase activity of METTL3, resulting in the increased m6A modification level of MYC mRNA, thereby promoting the self-renewal of GSCs.

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Fig. 1: The expression of transcription factor YY1 in GBM and its effect on the self-renewal of GSCs.
Fig. 2: YY1 accelerates the self-renewal of GSCs by promoting SENP1 expression.
Fig. 3: YY1 inhibits SUMO modification of METL3 by upregulating the expression of SENP1, thereby promoting the m6A modification of MYC.
Fig. 4: SENP1 accelerates the self-renewal of GSCs through the METTL3/MYC axis.
Fig. 5: YY1/SENP1/METTL3/MYC axis affects self-renewal of GSCs.
Fig. 6: YY1 promotes the tumorigenicity of GSCs through MYC in vivo.
Fig. 7: A schematic map showing the regulation of the YY1/SENP1/METTL3/MYC axis in the function of GSCs.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by the Sichuan Clinical Research Center for Neurosurgery, Luzhou Science and Technology Program (2020-JYJ-45), Science and Technology Foundation of Sichuan (2021YJ0430) and Luzhou Municipal People’s Government-Southwest Medical University Joint Project (2020LZXNYDJ33).

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Authors and Affiliations

  1. Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, P. R. China

    Jian You, Lilei Peng, Tangming Peng, Haiping He, Shan Zeng, Jizhong Han, Ligang Chen, Xiangguo Xia, Xiaobo Yang & Chuanhong Zhong

  2. Sichuan Clinical Research Center for Neurosurgery, 646000, Luzhou, P. R. China

    Jian You, Lilei Peng, Tangming Peng, Haiping He, Shan Zeng, Jizhong Han, Ligang Chen, Xiangguo Xia, Xiaobo Yang & Chuanhong Zhong

  3. Rheumatism Department, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, P. R. China

    Bei Tao

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Contributions

Conceived and designed the experiments: XBY, BT, and LLP. Performed experiments: YJ, HPH, and SZ. Performed experimental validation: JZH and LGC. Analyzed the data and conceived figures: XGX and CHZ. Wrote the manuscript: XBY, BT, and LLP. Revised the manuscript: YJ, TMP, and CHZ. All authors approved the final version of the manuscript.

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Correspondence to Xiaobo Yang or Chuanhong Zhong.

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You, J., Tao, B., Peng, L. et al. Transcription factor YY1 mediates self-renewal of glioblastoma stem cells through regulation of the SENP1/METTL3/MYC axis. Cancer Gene Ther 30, 683–693 (2023). https://doi.org/10.1038/s41417-022-00580-0

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