PMID- 36460215
OWN - NLM
STAT- MEDLINE
DCOM- 20230117
LR  - 20230117
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 194
DP  - 2023 Jan
TI  - Overactivated NRF2 induces pseudohypoxia in hepatocellular carcinoma by 
      stabilizing HIF-1alpha.
PG  - 347-356
LID - S0891-5849(22)01020-6 [pii]
LID - 10.1016/j.freeradbiomed.2022.11.039 [doi]
AB  - Hypoxia-inducible factor-1alpha (HIF-1alpha) is highly expressed/activated in most 
      hypoxic tumors including hepatocellular carcinoma (HCC). Another key 
      transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), is also 
      constitutively overactivated in HCC. In an attempt to determine whether HIF-1alpha 
      and NRF2 could play complementary roles in HCC growth and progression, we 
      investigated the crosstalk between these two transcription factors and underlying 
      molecular mechanisms in cultured HCC cells and experimentally induced 
      hepatocarcinogenesis as well as clinical settings. While silencing of HIF-1alpha in 
      HepG2 human hepatoma cells did not alter the protein expression of NRF2, NRF2 
      knockdown markedly reduced the nuclear accumulation of HIF-1alpha without influencing 
      its mRNA expression. In diethylnitrosamine-induced hepatocarcinogenesis in wild 
      type mice, there was elevated NRF2 expression with concomitant upregulation of 
      HIF-1alpha. However, this was abolished in Nrf2 knockout mice. NRF2 and HIF-1alpha 
      co-localized and physically interacted with each other as assessed by in situ 
      proximity ligation and immunoprecipitation assays. In addition, the interaction 
      between NRF2 and HIF-1alpha as well as their overexpression was found in tumor 
      specimens obtained from HCC patients. In normoxia, HIF-1alpha undergoes hydroxylation 
      by a specific HIF-prolyl hydroxylase domain protein (PHD), which facilitates 
      ubiquitination and proteasomal degradation of HIF-1alpha. NRF2 contributes to 
      pseudohypoxia, by directly binding to the oxygen-dependent degradation (ODD) 
      domain of HIF-1alpha, which hampers the PHD2-mediated hydroxylation, concomitant 
      recruitment of von-Hippel-Lindau and ubiquitination of HIF-1alpha.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Zheng, Jie
AU  - Zheng J
AD  - College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
FAU - Kim, Su-Jung
AU  - Kim SJ
AD  - Department of Molecular Medicine and Biopharmaceutical Science, Graduate School 
      of Convergence Science and Technology, Seoul National University, Seoul 08826, 
      South Korea.
FAU - Saeidi, Soma
AU  - Saeidi S
AD  - Department of Molecular Medicine and Biopharmaceutical Science, Graduate School 
      of Convergence Science and Technology, Seoul National University, Seoul 08826, 
      South Korea.
FAU - Kim, Seong Hoon
AU  - Kim SH
AD  - College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
FAU - Fang, Xizhu
AU  - Fang X
AD  - College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
FAU - Lee, Yeon-Hwa
AU  - Lee YH
AD  - College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
FAU - Guillen-Quispe, Yanymee N
AU  - Guillen-Quispe YN
AD  - Department of Molecular Medicine and Biopharmaceutical Science, Graduate School 
      of Convergence Science and Technology, Seoul National University, Seoul 08826, 
      South Korea.
FAU - Ngo, Hoang Kieu Chi
AU  - Ngo HKC
AD  - College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
FAU - Kim, Do-Hee
AU  - Kim DH
AD  - Department of Chemistry, College of Convergence and Integrated Science, Kyonggi 
      University, Suwon 16627, South Korea.
FAU - Kim, Doojin
AU  - Kim D
AD  - Department of Surgery, Gachon University Gil Medical Center, Gachon University 
      School of Medicine, Incheon 21565, South Korea.
FAU - Surh, Young-Joon
AU  - Surh YJ
AD  - College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Cancer 
      Research Institute, Seoul National University, Seoul 03080, South Korea. 
      Electronic address: surh@snu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221130
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Carcinoma, Hepatocellular/chemically induced/genetics/metabolism
MH  - Cell Line
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics
MH  - *Liver Neoplasms/genetics/metabolism
MH  - NF-E2-Related Factor 2/genetics
OTO - NOTNLM
OT  - HIF-1alpha
OT  - Hepatocellular carcinoma
OT  - Hypoxia
OT  - NRF2
OT  - Pseudohypoxia
EDAT- 2022/12/03 06:00
MHDA- 2023/01/10 06:00
CRDT- 2022/12/02 19:25
PHST- 2022/11/20 00:00 [received]
PHST- 2022/11/28 00:00 [accepted]
PHST- 2022/12/03 06:00 [pubmed]
PHST- 2023/01/10 06:00 [medline]
PHST- 2022/12/02 19:25 [entrez]
AID - S0891-5849(22)01020-6 [pii]
AID - 10.1016/j.freeradbiomed.2022.11.039 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2023 Jan;194:347-356. doi: 
      10.1016/j.freeradbiomed.2022.11.039. Epub 2022 Nov 30.