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

  • Oncogene. 2022 Aug;41(33):4018-4027. doi: 10.1038/s41388-022-02403-w.
Ming Gao   #  1  2 ,  Zijuan Qi   #  3 ,  Min Deng  4 ,  Hongyang Huang  5 ,  Zhijie Xu  6 ,  Guijie Guo  7 ,  Jiajun Jing  1  2 ,  Xiaofeng Huang  1  2 ,  Ming Xu  1  2 ,  Jake A Kloeber  7  8 ,  Sijin Liu  1  2 ,  Jinzhou Huang  9 ,  Zhenkun Lou  10 ,  Jinxiang Han  11
Affiliations
  • 1. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 100085, Beijing, China.
  • 2. University of Chinese Academy of Sciences, 100049, Beijing, China.
  • 3. Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China.
  • 4. State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, Chinese Academy of Medical Sciences, 100021, Beijing, China.
  • 5. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
  • 6. Department of Pathology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • 7. Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 8. Mayo Clinic Medical Scientist Training Program, Mayo Clinic, Rochester, MN, 55905, USA.
  • 9. Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. [email protected].
  • 10. Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA. [email protected].
  • 11. Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China. [email protected].
  • # Contributed equally.
PMID: 35821281 DOI: 10.1038/s41388-022-02403-w
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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