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The deubiquitinase USP7 regulates oxidative stress through stabilization of HO-1.
Gao, Ming; Qi, Zijuan; Deng, Min; Huang, Hongyang; Xu, Zhijie; Guo, Guijie; Jing, Jiajun; Huang, Xiaofeng; Xu, Ming; Kloeber, Jake A; Liu, Sijin; Huang, Jinzhou; Lou, Zhenkun; Han, Jinxiang.
Afiliación
  • Gao M; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 100085, Beijing, China.
  • Qi Z; University of Chinese Academy of Sciences, 100049, Beijing, China.
  • Deng M; Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Ji'nan, 250014, Shandong, China.
  • Huang H; State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, Chinese Academy of Medical Sciences, 100021, Beijing, China.
  • Xu Z; Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 999077, China.
  • Guo G; Department of Pathology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
  • Jing J; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
  • Huang X; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 100085, Beijing, China.
  • Xu M; University of Chinese Academy of Sciences, 100049, Beijing, China.
  • Kloeber JA; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 100085, Beijing, China.
  • Liu S; University of Chinese Academy of Sciences, 100049, Beijing, China.
  • Huang J; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, 100085, Beijing, China.
  • Lou Z; University of Chinese Academy of Sciences, 100049, Beijing, China.
  • Han J; Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
Oncogene ; 41(33): 4018-4027, 2022 08.
Article en En | MEDLINE | ID: mdl-35821281
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arsénico / Carcinoma Hepatocelular / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arsénico / Carcinoma Hepatocelular / Neoplasias Hepáticas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido