GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone
GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone
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GSTZ1-1 缺陷通过肿瘤代谢物琥珀酰丙酮的积累激活 HCC 中的 NRF2/IGF1R 轴
DOI：
10.15252/embj.2019101964
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发表时间：
2019-06-28
期刊：
影响因子：
11.4
通讯作者：
Tang, Ni
中科院分区：
文献类型：
--
作者：
Yang, Fan;Li, Jingjing;Tang, Ni
IGF 1 R信号传导在癌症的恶性进展中非常重要。然而，IGF 1 R的过度表达在HCC中尚未得到适当的评估。在此，我们发现，GSTZ 1 -1，在苯丙氨酸/酪氨酸催化剂的酶，在肝癌下调，其表达与IGF 1 R呈负相关。从机制上讲，GSTZ 1 -1缺陷导致琥珀酰丙酮积累，KEAP 1的烷基化修饰和NRF 2激活，从而通过将SP1募集到其启动子来促进IGF 1 R转录。此外，IGF 1 R或NRF 2的抑制显著抑制GSTZ 1敲除的体内促肿瘤作用。这些发现证实琥珀酰丙酮是肿瘤代谢物，GSTZ 1 -1通过抑制肝癌中的NRF 2/IGF 1 R轴而成为重要的肿瘤抑制因子。靶向NRF 2或IGF 1 R可能是该亚组HCC的有希望的治疗方法。
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.