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GSTZ 1‐1 Deficiency Activates NRF 2/ IGF 1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone
Author(s) -
Yang Fan,
Li Jingjing,
Deng Haijun,
Wang Yihao,
Lei Chong,
Wang Qiujie,
Xiang Jin,
Liang Li,
Xia Jie,
Pan Xuanming,
Li Xiaosong,
Long Quanxin,
Chang Lei,
Xu Ping,
Huang Ailong,
Wang Kai,
Tang Ni
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019101964
Subject(s) - christian ministry , beijing , china , viral hepatitis , hepatitis b , medicine , library science , virology , political science , computer science , law
The IGF 1R signaling is important in the malignant progression of cancer. However, overexpression of IGF 1R has not been properly assessed in HCC . Here, we revealed that GSTZ 1‐1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC , and its expression was negatively correlated with IGF 1R. Mechanistically, GSTZ 1‐1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP 1, and NRF 2 activation, thus promoting IGF 1R transcription by recruiting SP 1 to its promoter. Moreover, inhibition of IGF 1R or NRF 2 significantly inhibited tumor‐promoting effects of GSTZ1 knockout in vivo . These findings establish succinylacetone as an oncometabolite, and GSTZ 1‐1 as an important tumor suppressor by inhibiting NRF 2/ IGF 1R axis in HCC . Targeting NRF 2 or IGF 1R may be a promising treatment approach for this subset HCC .