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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Source data and reagents are available from the corresponding author upon reasonable request.
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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).
The authors declare no competing interests.
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