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O-GlcNAcylation of melanophilin enhances radiation resistance in glioblastoma via suppressing TRIM21 mediated ubiquitination

Abstract

The molecular mechanism of glioblastoma (GBM) radiation resistance remains poorly understood. The aim of this study was to elucidate the potential role of Melanophilin (MLPH) O-GlcNAcylation and the specific mechanism through which it regulates GBM radiotherapy resistance. We found that MLPH was significantly upregulated in recurrent GBM tumor tissues after ionizing radiation (IR). MLPH induced radiotherapy resistance in GBM cells and xenotransplanted human tumors through regulating the NF-κB pathway. MLPH was O-GlcNAcylated at the conserved serine 510, and radiation-resistant GBM cells showed higher levels of O-GlcNAcylation of MLPH. O-GlcNAcylation of MLPH protected its protein stability and tripartite motif containing 21(TRIM21) was identified as an E3 ubiquitin ligase promoting MLPH degradation whose interaction with MLPH was affected by O-GlcNAcylation. Our data demonstrate that MLPH exerts regulatory functions in GBM radiation resistance by promoting the NF-κB signaling pathway and that O-GlcNAcylation of MLPH both stabilizes and protects it from TRIM21-mediated ubiquitination. These results identify a potential mechanism of GBM radiation resistance and suggest a potential therapeutic strategy for GBM treatment.

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Fig. 1: MLPH is significantly upregulated in GBM resistant to radiotherapy.
Fig. 2: MLPH inhibition sensitizes radiation resistant GBM to IR.
Fig. 3: MLPH overexpression confers GBM resistance to IR.
Fig. 4: MLPH is O-GlcNAcylated by OGT at the conserved serine 510.
Fig. 5: O-GlcNAcylation of MLPH promotes its protein stability.
Fig. 6: O-GlcNAcylation protects MLPH from TRIM21 mediated ubiquitination.
Fig. 7: MLPH regulates GBM radiotherapy resistance through the NF-κB signal pathway.
Fig. 8: Pharmacological decreasing O-GlcNAcylation of MLPH improves the radiotherapy sensitivity of GBM.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (82120108018 and 81972153); China Postdoctoral Science Foundation (2021M701495); Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, Grant No. JX10231803); Gusu School, Nanjing Medical University (GSKY202201010); Natural Science Foundation of Jiangsu Province for Distinguished Young Scholars (BK20220727); National Natural Science Youth Fund of China (82303835).

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Conception and design: JJ, YT and LX; development of methodology: JJ, YT and LX; acquisition of data: LX, ZT and YY; analysis and interpretation of data: LX, TW, PZ, WG, BG, LZ, WC, XW and YT; writing the manuscript: LX; administrative, technical, or material support: JJ, YT and LX. All authors read and approved the final paper.

Corresponding authors

Correspondence to Yiming Tu or Jing Ji.

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The human brain tissues were obtained from the Department of Neurosurgery at the First Affiliated Hospital of Nanjing Medical University, and was approved by the Institutional Review Board (2021-SR-202). The animal study was reviewed and approved by Nanjing Medical University’ s Institutional Animal Care and Use Committee (IACUC).

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Xu, L., Ye, Y., Tao, Z. et al. O-GlcNAcylation of melanophilin enhances radiation resistance in glioblastoma via suppressing TRIM21 mediated ubiquitination. Oncogene 43, 61–75 (2024). https://doi.org/10.1038/s41388-023-02881-6

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  • DOI: https://doi.org/10.1038/s41388-023-02881-6

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