PMID- 34815381
OWN - NLM
STAT- MEDLINE
DCOM- 20220322
LR  - 20221025
IS  - 2059-3635 (Electronic)
IS  - 2095-9907 (Print)
IS  - 2059-3635 (Linking)
VI  - 6
IP  - 1
DP  - 2021 Nov 24
TI  - HACE1-mediated NRF2 activation causes enhanced malignant phenotypes and decreased 
      radiosensitivity of glioma cells.
PG  - 399
LID - 10.1038/s41392-021-00793-z [doi]
LID - 399
AB  - 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.
CI  - (c) 2021. The Author(s).
FAU - Da, Chenxing
AU  - Da C
AD  - Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of 
      Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 
      710061, Xi'an, People's Republic of China.
AD  - Shanxi Provincial Crops Hospital of Chinese People's Armed Police Force, 710054, 
      Xi'an, People's Republic of China.
FAU - Pu, Jun
AU  - Pu J
AD  - Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of 
      Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 
      710061, Xi'an, People's Republic of China.
FAU - Liu, Zhe
AU  - Liu Z
AD  - Department of Diagnostic Radiology, The First Affiliated Hospital of Xi'an 
      Jiaotong University, 710061, Xi'an, People's Republic of China.
FAU - Wei, Jing
AU  - Wei J
AD  - Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of 
      Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 
      710061, Xi'an, People's Republic of China.
FAU - Qu, Yiping
AU  - Qu Y
AD  - Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of 
      Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 
      710061, Xi'an, People's Republic of China.
FAU - Wu, Yongxing
AU  - Wu Y
AD  - Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong 
      University, 710061, Xi'an, People's Republic of China.
FAU - Shi, Bingyin
AU  - Shi B
AD  - Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of 
      Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 
      710061, Xi'an, People's Republic of China.
FAU - Yang, Jian
AU  - Yang J
AD  - Department of Diagnostic Radiology, The First Affiliated Hospital of Xi'an 
      Jiaotong University, 710061, Xi'an, People's Republic of China. 
      yj1118@mail.xjtu.edu.cn.
FAU - He, Nongyue
AU  - He N
AD  - State Key Laboratory of Bioelectronics, Southeast University, 210096, Nanjing, 
      People's Republic of China. nyhe1958@163.com.
FAU - Hou, Peng
AU  - Hou P
AD  - Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of 
      Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 
      710061, Xi'an, People's Republic of China. phou@xjtu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211124
PL  - England
TA  - Signal Transduct Target Ther
JT  - Signal transduction and targeted therapy
JID - 101676423
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - EC 2.3.2.26 (HACE1 protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Cell Line, Tumor
MH  - Glioma/genetics/*metabolism/radiotherapy
MH  - Humans
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - *Radiation Tolerance
MH  - Ubiquitin-Protein Ligases/genetics/*metabolism
PMC - PMC8611003
COIS- The authors declare no competing interests.
EDAT- 2021/11/25 06:00
MHDA- 2022/03/23 06:00
PMCR- 2021/11/24
CRDT- 2021/11/24 05:49
PHST- 2019/11/05 00:00 [received]
PHST- 2021/10/11 00:00 [accepted]
PHST- 2021/08/20 00:00 [revised]
PHST- 2021/11/24 05:49 [entrez]
PHST- 2021/11/25 06:00 [pubmed]
PHST- 2022/03/23 06:00 [medline]
PHST- 2021/11/24 00:00 [pmc-release]
AID - 10.1038/s41392-021-00793-z [pii]
AID - 793 [pii]
AID - 10.1038/s41392-021-00793-z [doi]
PST - epublish
SO  - Signal Transduct Target Ther. 2021 Nov 24;6(1):399. doi: 
      10.1038/s41392-021-00793-z.