HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells.
HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells.
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HACE1 介导的 NRF2 激活导致神经胶质瘤细胞的恶性表型增强和放射敏感性降低。
DOI：
10.1038/s41392-021-00793-z
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发表时间：
2021-11-24
影响因子：
39.3
通讯作者：
Hou P
中科院分区：
文献类型：
--
作者：
Da C;Pu J;Liu Z;Wei J;Qu Y;Wu Y;Shi B;Yang J;He N;Hou P
HACE1是一种E3泛素蛋白连接酶，经常失活，并已被证明是不同类型癌症中的假定肿瘤抑制因子。然而，其在胶质瘤中的作用仍然难以捉摸。在这里，我们观察到与对照受试者相关的胶质瘤中的HACE1表达增加，并且发现高HACE1表达与WHO III级和IV级患者以及接受放射治疗的低级别胶质瘤（LGG）患者的不良预后具有强相关性。在体外和体内实验中，HACE1基因的敲低明显抑制了胶质瘤细胞的恶性行为，而HACE1基因的异位表达促进了胶质瘤细胞的生长。进一步的研究表明，HACE1通过与另一种E3连接酶KEAP 1竞争性结合核因子红细胞2相关因子2（NRF 2），增强了NRF 2的蛋白稳定性。此外，HACE1还促进内部核糖体进入位点（IRES）介导的NRF2的mRNA翻译。这些效应不依赖于其E3连接酶活性。最后，我们证明了HACE1通过激活NRF2显著降低细胞ROS水平，从而降低胶质瘤细胞对辐射的反应。综上所述，我们的数据表明，HACE1通过激活NRF2导致胶质瘤细胞恶性表型的增强和放射敏感性的降低，并表明其可能作为胶质瘤的预后因子和潜在的治疗靶点。
HACE1, an E3 ubiquitin-protein ligase, is frequently inactivated and has been evidenced as a putative tumor suppressor in different types of cancer. However, its role in glioma remains elusive. Here, we observed increased expression of HACE1 in gliomas related to control subjects, and found a strong correlation of high HACE1 expression with poor prognosis in patients with WHO grade III and IV as well as low-grade glioma (LGG) patients receiving radiotherapy. HACE1 knockdown obviously suppressed malignant behaviors of glioma cells, while ectopic expression of HACE1 enhanced cell growth in vitro and in vivo. Further studies revealed that HACE1 enhanced protein stability of nuclear factor erythroid 2-related factor 2 (NRF2) by competitively binding to NRF2 with another E3 ligase KEAP1. Besides, HACE1 also promoted internal ribosome entry site (IRES)-mediated mRNA translation of NRF2. These effects did not depend on its E3 ligase activity. Finally, we demonstrated that HACE1 dramatically reduced cellular ROS levels by activating NRF2, thereby decreasing the response of glioma cells to radiation. Altogether, our data demonstrate that HACE1 causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells by activating NRF2, and indicate that it may act as the role of prognostic factor and potential therapeutic target in glioma.
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影响因子：
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作者：
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