E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression
E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression
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DOI：
10.1038/s41388-023-02644-3
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发表时间：
2023-03
期刊：
影响因子：
8
通讯作者：
Peijun Zhou;Xingzhi Peng;Siyuan Tang;Kun Zhang;Zhikai Tan;Dan Li;Liang Shen;Jinwu Peng;
中科院分区：
文献类型：
--
作者：
Peijun Zhou;Xingzhi Peng;Siyuan Tang;Kun Zhang;Zhikai Tan;Dan Li;Liang Shen;Jinwu Peng;
胶质母细胞瘤（GBM）是最常见的恶性胶质瘤，复发率高，预后差。然而，GBM恶性发展的分子机制尚不清楚。在本研究中，我们通过对临床原发性和复发性胶质瘤样本进行基于串联质量标签（TMT）的定量蛋白质组学分析，发现复发性胶质瘤样本中表达了异常的E3连接酶MAEA。生物信息学分析结果显示，MAEA的高表达与胶质瘤和GBM的复发和不良预后有关。功能研究表明，MAEA可促进肿瘤细胞增殖、侵袭、干性及对替莫唑胺（TMZ）的耐药。机制上，数据表明MAEA靶向脯氨酸羟化酶结构域3 (PHD3) K159，促进其k48连锁的多泛素化和降解，从而增强HIF-1α的稳定性，从而通过上调CD133促进GBM细胞的干性和TMZ抗性。体内实验进一步证实，敲除MAEA可抑制GBM异种移植瘤的生长。综上所述，MAEA通过降解PHD3增强HIF-1α/CD133的表达，促进GBM的恶性进展。
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.