m<SUP>6</SUP>A demethylation of <i>FOSL1</i> mRNA protects hepatoma cells against necrosis under glucose deprivation

作者全名："Wang, Chun-Rui; Gong, Jun-Hua; Zhao, Zhi-Bo; Zhu, Qian; Shu, Bian; Hu, Jie-Jun; Cai, Dong; Liu, Xin-Yi; Dai, Xin; Qiu, Chan; Gong, Jian-Ping; Zhong, Guo-Chao"

作者地址："[Wang, Chun-Rui] Chongqing Med Univ, Affiliated Hosp 2, Key Lab Mol Biol Infect Dis, Chinese Minist Educ,Inst Viral Hepatitis,Dept Infe, Chongqing, Peoples R China; [Gong, Jun-Hua; Zhao, Zhi-Bo; Shu, Bian; Hu, Jie-Jun; Cai, Dong; Liu, Xin-Yi; Dai, Xin; Gong, Jian-Ping; Zhong, Guo-Chao] Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Chongqing, Peoples R China; [Zhu, Qian] Chongqing Med Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Chongqing, Peoples R China; [Qiu, Chan] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol, Chongqing, Peoples R China"

通信作者："Zhong, GC (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Chongqing, Peoples R China."

来源：CELL DEATH AND DIFFERENTIATION

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001226823500002

JCR分区：Q1

影响因子：12.4

年份：2024

卷号：31

期号：8

开始页：1029

结束页：1043

文献类型：Article

关键词：　

摘要："Stress-adaptive mechanisms enabling cancer cells to survive under glucose deprivation remain elusive. N-6-methyladenosine (m(6)A) modification plays important roles in determining cancer cell fate and cellular stress response to nutrient deficiency. However, whether m(6)A modification functions in the regulation of cancer cell survival under glucose deprivation is unknown. Here, we found that glucose deprivation reduced m(6)A modification levels. Increasing m(6)A modification resulted in increased hepatoma cell necrosis under glucose deprivation, whereas decreasing m(6)A modification had an opposite effect. Integrated m(6)A-seq and RNA-seq revealed potential targets of m(6)A modification under glucose deprivation, including the transcription factor FOSL1; further, glucose deprivation upregulated FOSL1 by inhibiting FOSL1 mRNA decay in an m(6)A-YTHDF2-dependent manner through reducing m(6)A modification in its exon1 and 5'-UTR regions. Functionally, FOSL1 protected hepatoma cells against glucose deprivation-induced necrosis in vitro and in vivo. Mechanistically, FOSL1 transcriptionally repressed ATF3 by binding to its promoter. Meanwhile, ATF3 and MAFF interacted via their leucine zipper domains to form a heterodimer, which competed with NRF2 for binding to antioxidant response elements in the promoters of NRF2 target genes, thereby inhibiting their transcription. Consequently, FOSL1 reduced the formation of the ATF3-MAFF heterodimer, thereby enhancing NRF2 transcriptional activity and the antioxidant capacity of glucose-deprived-hepatoma cells. Thus, FOSL1 alleviated the necrosis-inducing effect of glucose deprivation-induced reactive oxygen species accumulation. Collectively, our study uncovers the protective role of m(6)A-FOSL1-ATF3 axis in hepatoma cell necrosis under glucose deprivation, and may provide new targets for cancer therapy."

基金机构：National Natural Science Foundation of China [82203391]; China Postdoctoral Science Foundation [2021M700638]; Special Funding for Postdoctoral Research Project of Chongqing [2021XM2043]

基金资助正文："This study was supported by grants from the National Natural Science Foundation of China (Grant number 82203391), China Postdoctoral Science Foundation (Project number: 2021M700638), and the Special Funding for Postdoctoral Research Project of Chongqing (Grant No. 2021XM2043). The funding supporters had no role in study design, data acquisition and analysis, decision to publish, or the preparation of the manuscript."