Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.
Department of Infectious Diseases, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
EMBO J. 2019 Aug 1;38(15):e101964. doi: 10.15252/embj.2019101964. Epub 2019 Jun 28.
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.
IGF1R 信号通路在癌症的恶性进展中很重要。然而，IGF1R 的过表达在 HCC 中并未得到适当评估。在这里，我们揭示了 GSTZ1-1，苯丙氨酸/酪氨酸分解代谢中的酶，在 HCC 中下调，其表达与 IGF1R 呈负相关。从机制上讲，GSTZ1-1 的缺乏导致琥珀酰丙酮积累、KEAP1 的烷化修饰和 NRF2 的激活，从而通过招募 SP1 到其启动子来促进 IGF1R 的转录。此外，抑制 IGF1R 或 NRF2 显著抑制了 GSTZ1 缺失在体内的促肿瘤作用。这些发现确立了琥珀酰丙酮作为一种致癌代谢物，GSTZ1-1 通过抑制 HCC 中的 NRF2/IGF1R 轴作为一种重要的肿瘤抑制因子。针对 NRF2 或 IGF1R 可能是治疗这部分 HCC 的一种很有前途的方法。
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