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

Abstract

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.

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Fig. 1: USP7 interacts with and deubiquitinates HO-1.
Fig. 2: USP7 regulates low-dose arsenic-triggered oxidative damage through HO-1.
Fig. 3: Deubiquitination of HO-1 by USP7 is important for arsenic-induced oxidative damage.
Fig. 4: Ubiquitination of USP7 promotes the interaction between USP7 and HO-1 under arsenic exposure.
Fig. 5: USP7 and HO-1 is critical for liver tumor growth in vivo and in vitro.
Fig. 6: USP7 and HO-1 are high expressed and positively correlated in the tumor samples of HCC patients.

Data availability

Research data is available upon request. No data was deposited to databases.

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Acknowledgements

This research was supported by National Natural Science Foundation of China (Grant no. 22076212), Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB2004), Science Fund for Creative Research Groups of the National Natural Science Foundation of China (22021003) and Youth Innovation Promotion Association of CAS (2021040).

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MG and ZQ designed and conducted experiments, analyzed data and wrote the paper; HH, MD, ZX, GG, JJ, XH, MX, JAK and SL provided technical and data analysis assistance. JHuang, ZL and JHan conceived and supervised the project, designed experiments, and analyzed data.

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Correspondence to Jinzhou Huang, Zhenkun Lou or Jinxiang Han.

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Gao, M., Qi, Z., Deng, M. et al. The deubiquitinase USP7 regulates oxidative stress through stabilization of HO-1. Oncogene 41, 4018–4027 (2022). https://doi.org/10.1038/s41388-022-02403-w

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