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Abstract
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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1 The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, Xi’an, People’s Republic of China (GRID:grid.452438.c) (ISNI:0000 0004 1760 8119); Shanxi Provincial Crops Hospital of Chinese People’s Armed Police Force, Xi’an, People’s Republic of China (GRID:grid.452438.c)
2 The First Affiliated Hospital of Xi’an Jiaotong University, Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, Xi’an, People’s Republic of China (GRID:grid.452438.c) (ISNI:0000 0004 1760 8119)
3 The First Affiliated Hospital of Xi’an Jiaotong University, Department of Diagnostic Radiology, Xi’an, People’s Republic of China (GRID:grid.452438.c) (ISNI:0000 0004 1760 8119)
4 The First Affiliated Hospital of Xi’an Jiaotong University, Department of Neurosurgery, Xi’an, People’s Republic of China (GRID:grid.452438.c) (ISNI:0000 0004 1760 8119)
5 Southeast University, State Key Laboratory of Bioelectronics, Nanjing, People’s Republic of China (GRID:grid.263826.b) (ISNI:0000 0004 1761 0489)