2. Academic Validation
  3. E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression

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

  • Oncogene. 2023 Mar 7. doi: 10.1038/s41388-023-02644-3.
Peijun Zhou # 1 2,  Xingzhi Peng # 1 2,  Siyuan Tang 1,  Kun Zhang 1,  Zhikai Tan 3,  Dan Li 3,  Liangfang Shen 1,  Jinwu Peng 4 5,  Lifang Yang 6 7 8
Affiliations

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.
  • 2 Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, 410078, China.
  • 3 Institute of Molecular Medicine and Oncology, College of Biology, Hunan University, Changsha, 410012, China.
  • 4 Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410078, China. [email protected].
  • 5 Department of Pathology, Xiangya Changde Hospital, Changde, 415000, China. [email protected].
  • 6 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. [email protected].
  • 7 Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, 410078, China. [email protected].
  • 8 Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. [email protected].
  • # Contributed equally.
PMID: 36882523 DOI: 10.1038/s41388-023-02644-3
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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