Journal
ONCOGENE
Volume 41, Issue 33, Pages 4018-4027Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-022-02403-w
Keywords
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Funding
- National Natural Science Foundation of China [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]
- Youth Innovation Promotion Association of CAS [2021040]
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The deubiquitinase USP7 plays a key role in controlling redox homeostasis by promoting HO-1 deubiquitination and stabilization in hepatocytes. USP7 inhibitor might be a potential therapeutic agent for treating HO-1 overexpressed liver cancers.
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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