The deubiquitinase USP7 regulates oxidative stress through stabilization of HO-1.

Ming Gao, Zijuan Qi, Min Deng, Hongyang Huang, Zhijie Xu, Guijie Guo, Jiajun Jing, Xiaofeng Huang, Ming Xu, Jake A Kloeber, Sijin Liu, Jinzhou Huang, Zhenkun Lou, Jinxiang Han

Oncogene 2022 Aug

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Heme oxygenase-1 (HO-1) is an inducible heme degradation enzyme that plays a cytoprotective role against various oxidative and inflammatory stresses. However, it has also been shown to exert an important role in cancer progression through a variety of mechanisms. Although transcription factors such as Nrf2 are involved in HO-1 regulation, the posttranslational modifications of HO-1 after oxidative insults and the underlying mechanisms remain unexplored. Here, we screened and identified that the deubiquitinase USP7 plays a key role in the control of redox homeostasis through promoting HO-1 deubiquitination and stabilization in hepatocytes. We used low-dose arsenic as a stress model which does not affect the transcriptional level of HO-1, and found that the interaction between USP7 and HO-1 is increased after arsenic exposure, leading to enhanced HO-1 expression and attenuated oxidative damages. Furthermore, HO-1 protein is ubiquitinated at K243 and subjected to degradation under resting conditions; whereas when after arsenic exposure, USP7 itself can be ubiquitinated at K476, thereafter promoting the binding between USP7 and HO-1, finally leading to enhanced HO-1 deubiquitination and protein accumulation. Moreover, depletion of USP7 and HO-1 inhibit liver tumor growth in vivo, and USP7 positively correlates with HO-1 protein level in clinical human hepatocellular carcinoma (HCC) specimens. In summary, our findings reveal a critical role of USP7 as a HO-1 deubiquitinating enzyme in the regulation of oxidative stresses, and suggest that USP7 inhibitor might be a potential therapeutic agent for treating HO-1 overexpressed liver cancers. © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Ming Gao, Zijuan Qi, Min Deng, Hongyang Huang, Zhijie Xu, Guijie Guo, Jiajun Jing, Xiaofeng Huang, Ming Xu, Jake A Kloeber, Sijin Liu, Jinzhou Huang, Zhenkun Lou, Jinxiang Han. The deubiquitinase USP7 regulates oxidative stress through stabilization of HO-1. Oncogene. 2022 Aug;41(33):4018-4027