HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased radiosensitivity of glioma cells

• Published in: Signal transduction and targeted therapy Vol. 6; no. 1; pp. 399 - 12
• Main Authors: Da, Chenxing, Pu, Jun, Liu, Zhe, Wei, Jing, Qu, Yiping, Wu, Yongxing, Shi, Bingyin, Yang, Jian, He, Nongyue, Hou, Peng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.11.2021; Nature Publishing Group
• Subjects: 631/337; 631/67; Brain cancer; Brain tumors; Cancer Research; Cancer therapies; Cell Biology; Cell cycle; Cell growth; Ectopic expression; Genomes; Glioma; Glioma cells; Internal Medicine; Internal ribosome entry site; Laboratories; Medical prognosis; Medicine; Medicine & Public Health; mRNA; Oncology; Oxidative stress; Pathology; Patients; Phenotypes; Proteins; Radiation therapy; Radiosensitivity; Signal transduction; Tumor suppressor genes; Tumors; Ubiquitin; Ubiquitin-protein ligase
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-021-00793-z

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.