Open AccessMild Oxidative Stress Reduces NRF2 SUMOylation to Promote Kras/Lkb1/Keap1 Mutant Lung Adenocarcinoma Cell Migration and Invasion
Author(s) -
Jiaqian Xu,
Haoyan Guo,
Zhengcao Xing,
Wenlong Zhang,
Jianli He,
Jinke Cheng,
Rong Cai
Publication year - 2020
Publication title -
oxidative medicine and cellular longevity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.494
H-Index - 93
eISSN - 1942-0900
pISSN - 1942-0994
DOI - 10.1155/2020/6240125
Subject(s) - sumo protein , oxidative stress , keap1 , microbiology and biotechnology , transcription factor , cell , cancer research , reactive oxygen species , biology , cell migration , chemistry , biochemistry , ubiquitin , gene
Nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor for cell adaptation and defense against oxidative stress. NRF2 activation confers Kras / Lkb1 / Keap1 (KLK) mutant tumor cells with greater resistance to oxidative insults. We previously reported that SUMOylation at lysine residue 110 is important for the ability of NRF2 to promote reactive oxygen species (ROS) clearance in hepatocellular carcinoma. In this study, we investigated whether SUMOylation is necessary for the ability of NRF2 to inhibit KLK lung adenocarcinoma (LUAD) cell migration and invasion. Our experiments showed that mild oxidative stress reduced NRF2 SUMOylation, which promoted KLK LUAD cell migration and invasion. Mechanistically, NRF2 SUMOylation increased the antioxidant ability of NRF2 and reduced cellular ROS levels, mainly by transcriptionally activating Cat in KLK LUAD cells. With reduced NRF2 SUMOylation, increased ROS acted as signaling molecules to activate the JNK/c-Jun axis, which enhanced cell mobility and cell adhesion, to promote LUAD cell migration and invasion. Taken together, the results of this study reveal a novel signaling process in which reduced NRF2 SUMOylation permits increased KLK LUAD cell migration and invasion under mild oxidative stress.