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

被引：21
作者：
Da, Chenxing [1 ,2 ,6 ]
Pu, Jun [1 ,2 ]
Liu, Zhe [3 ]
Wei, Jing [1 ,2 ]
Qu, Yiping [1 ,2 ]
Wu, Yongxing [4 ]
Shi, Bingyin [1 ,2 ]
Yang, Jian [3 ]
He, Nongyue [5 ]
Hou, Peng [1 ,2 ]
机构：
[1] Xi An Jiao Tong Univ, Key Lab Tumor Precis Med Shaanxi Prov, Affiliated Hosp 1, Xian 710061, Peoples R China
[2] Xi An Jiao Tong Univ, Dept Endocrinol, Affiliated Hosp 1, Xian 710061, Peoples R China
[3] Xi An Jiao Tong Univ, Dept Diagnost Radiol, Affiliated Hosp 1, Xian 710061, Peoples R China
[4] Xi An Jiao Tong Univ, Dept Neurosurg, Affiliated Hosp 1, Xian 710061, Peoples R China
[5] Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Peoples R China
[6] Shanxi Prov Crops Hosp Chinese Peoples Armed Poli, Xian 710054, Peoples R China
来源：
SIGNAL TRANSDUCTION AND TARGETED THERAPY | 2021年 / 6卷 / 01期
基金：
中国国家自然科学基金;
关键词：
LIGASE HACE1; SIGNALING PATHWAY; CANCER CELLS; INHIBITION; MIGRATION; RAC1; PSEUDOPROGRESSION; UBIQUITYLATION; CHEMOTHERAPY; EXPRESSION;
D O I：
10.1038/s41392-021-00793-z
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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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页数：12
相关论文
共 49 条
[1]  
Afra D, 2002, LANCET, V359, P1011
[2]   The tumour suppressor HACE1 controls cell migration by regulating Rac1 degradation [J].
Castillo-Lluva, S. ;
Tan, C-T ;
Daugaard, M. ;
Sorensen, P. H. B. ;
Malliri, A. .
ONCOGENE, 2013, 32 (13) :1735-1742
[3]   Nox1-dependent reactive oxygen generation is regulated by Rac1 [J].
Cheng, Guangjie ;
Diebold, Becky A. ;
Hughes, Yasmin ;
Lambeth, J. David .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (26) :17718-17726
[4]   Dynamic expression of ZNF382 and its tumor-suppressor role in hepatitis B virus-related hepatocellular carcinogenesis [J].
Dang, Siwen ;
Zhou, Jingshi ;
Chen, Yijun ;
Chen, Pu ;
Ji, Meiju ;
Shi, Bingyin ;
Yang, Qi ;
Hou, Peng .
ONCOGENE, 2019, 38 (24) :4804-4819
[5]   Hace1 controls ROS generation of vertebrate Rac1-dependent NADPH oxidase complexes [J].
Daugaard, Mads ;
Nitsch, Roberto ;
Razaghi, Babak ;
McDonald, Lindsay ;
Jarrar, Ameer ;
Torrino, Stephanie ;
Castillo-Lluva, Sonia ;
Rotblat, Barak ;
Li, Liheng ;
Malliri, Angeliki ;
Lemichez, Emmanuel ;
Mettouchi, Amel ;
Berman, Jason N. ;
Penninger, Josef M. ;
Sorensen, Poul H. .
NATURE COMMUNICATIONS, 2013, 4
[6]   Uncovering and deciphering the pro-invasive role of HACE1 in melanoma cells [J].
El-Hachem, Najla ;
Habel, Nadia ;
Naiken, Tanesha ;
Bzioueche, Hanene ;
Cheli, Yann ;
Beranger, Guillaume E. ;
Jaune, Emilie ;
Rouaud, Florian ;
Nottet, Nicolas ;
Reinier, Frederic ;
Gaudel, Celine ;
Colosetti, Pascale ;
Bertolotto, Corine ;
Ballotti, Robert .
CELL DEATH AND DIFFERENTIATION, 2018, 25 (11) :2010-2022
[7]   Cost of migration: Invasion of malignant gliomas and implications for treatment [J].
Giese, A ;
Bjerkvig, R ;
Berens, ME ;
Westphal, M .
JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (08) :1624-1636
[8]   Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression [J].
Goka, E. T. ;
Lippman, M. E. .
ONCOGENE, 2015, 34 (42) :5395-5405
[9]   Internal ribosome entry sites in eukaryotic mRNA molecules [J].
Hellen, CUT ;
Sarnow, P .
GENES & DEVELOPMENT, 2001, 15 (13) :1593-1612
[10]   A comparison of individual and population-derived vascular input functions for quantitative DCE-MRI in rats [J].
Hormuth, David A., II ;
Skinner, Jack T. ;
Does, Mark D. ;
Yankeelov, Thomas E. .
MAGNETIC RESONANCE IMAGING, 2014, 32 (04) :397-401
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