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E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression

Oncogene volume 42, pages 1308–1320 (2023)Cite this article

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Abstract

Glioblastoma (GBM) is the most common malignant glioma, with a high recurrence rate and a poor prognosis. However, the molecular mechanism behind the malignant progression of GBM is still unclear. In the present study, through the tandem mass tag (TMT)-based quantitative proteomic analysis of clinical primary and recurrent glioma samples, we identified that aberrant E3 ligase MAEA was expressed in recurrent samples. The results of bioinformatics analysis showed that the high expression of MAEA was related to the recurrence and poor prognosis of glioma and GBM. Functional studies showed that MAEA could promote proliferation, invasion, stemness and temozolomide (TMZ) resistance. Mechanistically, the data indicated that MAEA targeted prolyl hydroxylase domain 3 (PHD3) K159 to promote its K48-linked polyubiquitination and degradation, thus enhancing the stability of HIF-1α, thereby promoting the stemness and TMZ resistance of GBM cells through upregulating CD133. The in vivo experiments further confirmed that knocking down MAEA could inhibit the growth of GBM xenograft tumors. In summary, MAEA enhances the expression of HIF-1α/CD133 through the degradation of PHD3 and promotes the malignant progression of GBM.

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Fig. 1: MAEA is highly expressed in glioma and is associated with glioma/GBM recurrence and poor prognosis.
Fig. 2: MAEA promotes the proliferation, invasion, stemness and TMZ resistance of GBM.
Fig. 3: PHD3 interacts with MAEA.
Fig. 4: MAEA targets PHD3 for ubiquitination and degradation at K159.
Fig. 5: PHD3 is involved in MAEA-mediated proliferation, invasion, stemness and TMZ resistance of GBM cells.
Fig. 6: MAEA regulates HIF-1α and CD133 by degrading PHD3.
Fig. 7: MAEA promotes tumor growth and TMZ resistance in vivo and there is a correlation among the expression of MAEA, PHD3, HIF-1α and CD133 in tumor tissue.

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Source data and reagents are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81974466), the Natural Science Foundation of Changsha, China (kq2202124), the Hunan Provincial Innovation Foundation for Postgraduate (No. CX20200382) and the Fundamental Research Funds for the Central Universities of Central South University (No. 1053320192726, 1053320212989).

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Author notes

  1. These authors contributed equally: Peijun Zhou, Xingzhi Peng.

Authors and Affiliations

  1. Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410078, China

    Peijun Zhou, Xingzhi Peng, Siyuan Tang, Kun zhang, Liangfang Shen & Lifang Yang

  2. Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, 410078, China

    Peijun Zhou, Xingzhi Peng & Lifang Yang

  3. Institute of Molecular Medicine and Oncology, College of Biology, Hunan University, Changsha, 410012, China

    Zhikai Tan & Dan Li

  4. Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410078, China

    Jinwu Peng

  5. Department of Pathology, Xiangya Changde Hospital, Changde, 415000, China

    Jinwu Peng

  6. Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Lifang Yang

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Contributions

PJZ and XZP designed the experiments, performed research and analyzed the data. SYT and LFS collected the tissue samples for proteomics analysis and analyzed data. KZ participated in xenograft experiments, processed tissue samples and analyzed data. ZKT generated constructs. JWP and LFY directed the research and analyzed the data. PJZ, DL and LFY wrote the manuscript. All authors approved final manuscript.

Corresponding authors

Correspondence to Jinwu Peng or Lifang Yang.

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The authors declare no competing interests.

Ethics statement

The experimental protocol was approved by the Ethics Committee of Xiangya Hospital of Central South University. Animals were raised and operated in accordance with the guidelines formulated by the Medical Research Animal Ethics Committee of Central South University.

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Zhou, P., Peng, X., Tang, S. et al. E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression. Oncogene 42, 1308–1320 (2023). https://doi.org/10.1038/s41388-023-02644-3

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