GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone.

Fan Yang,Chong Lei,Xuanming Pan,Qiujie Wang,Ni Tang,Jin Xiang,Li Liang,Haijun Deng,Quanxin Long,Lei Chang,Ailong Huang,Jingjing Li,Jie Xia,Ping Xu,Kai Wang,Yihao Wang,Xiaosong Li

doi:10.15252/embj.2019101964

Fan Yang, Chong Lei + Show 15 more

Open Access

https://doi.org/10.15252/embj.2019101964

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Abstract

The IGF1R signaling is important in the malignant progression of cancer. However, overexpression of IGF1R has not been properly assessed in HCC. Here, we revealed that GSTZ1‐1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC, and its expression was negatively correlated with IGF1R. Mechanistically, GSTZ1‐1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter. Moreover, inhibition of IGF1R or NRF2 significantly inhibited tumor‐promoting effects of GSTZ1 knockout in vivo. These findings establish succinylacetone as an oncometabolite, and GSTZ1‐1 as an important tumor suppressor by inhibiting NRF2/IGF1R axis in HCC. Targeting NRF2 or IGF1R may be a promising treatment approach for this subset HCC.

Highlights

The insulin-like growth factor (IGF) signaling axis is critical in the growth and development of various tissues
We explored the connection between activation of nuclear factor erythroid 2-related factor 2 (NRF2) and enhanced expression of IGF-1 receptor (IGF1R) induced by Glutathione S-transferase zeta 1-1 (GSTZ1-1) depletion
GSTZ1-1 overexpression decreased IGF1R promoter activity and protein level, whereas treatment with the NRF2 activator tertiary butylhydroquinone rescued these changes (Fig 6C). These results suggest that GSTZ1-1 affects the expression of IGF1R by regulating NRF2 activity

Summary

Introduction

The insulin-like growth factor (IGF) signaling axis is critical in the growth and development of various tissues. Increasing evidence shows that IGF1R and its ligands (IGF-1, IGF-2) play an important role in the development and progression of several cancers, including hepatocellular carcinoma (HCC) (Aleem et al, 2011; Pollak, 2012). In addition to altered glucose metabolism, changes in amino acid metabolism contribute to different aspects of tumorigenesis; for example, aberrant activation of the serine/glycine biosynthetic pathway is critical in cancer pathogenesis (Amelio et al, 2014). Restoring these altered metabolic pathways may be a new cancer therapeutic approach (Vander Heiden, 2011)

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