Qikai Sun1,2, Zechuan Zhang1,2, Yijun Lu1,2, Qiaoyu Liu1, Xiaoliang Xu1, Jianbo Xu2, Yang Liu1,2, Hailong Yu1, Decai Yu1, Beicheng Sun1,2,3. 1. Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. 2. Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 3. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Abstract
BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) exist in the tumor environment and are critically involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of self-renewal and maintenance of liver CSCs remain poorly understood. APPROACH AND RESULTS: We identified that xanthine oxidoreductase (XOR), which was expressed at low levels in human HCC samples and liver CSCs, restrained HCC formation and chemoresistance by attenuating liver CSC propagation. Mechanistically, XOR physically interacts with ubiquitin-specific peptidase 15 (USP15), thereby promoting deubiquitination of Kelch-like ECH associated protein 1 (KEAP1) to stabilize its expression, which leads to degradation of Nrf2 (nuclear factor erythroid 2-related factor 2) through ubiquitination and subsequently reactive oxygen species accumulation in liver CSCs. Finally, our data reveal that XOR promotes USP15-mediated Nrf2-KEAP1 signaling to block liver CSCs and tumor propagation. CONCLUSION: We identified that XOR may represent a potential therapeutic target for clinical intervention in HCC driven by liver CSCs.
BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) exist in the tumor environment and are critically involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of self-renewal and maintenance of liver CSCs remain poorly understood. APPROACH AND RESULTS: We identified that xanthine oxidoreductase (XOR), which was expressed at low levels in humanHCC samples and liver CSCs, restrained HCC formation and chemoresistance by attenuating liver CSC propagation. Mechanistically, XOR physically interacts with ubiquitin-specific peptidase 15 (USP15), thereby promoting deubiquitination of Kelch-like ECH associated protein 1 (KEAP1) to stabilize its expression, which leads to degradation of Nrf2 (nuclear factor erythroid 2-related factor 2) through ubiquitination and subsequently reactive oxygen species accumulation in liver CSCs. Finally, our data reveal that XOR promotes USP15-mediated Nrf2-KEAP1 signaling to block liver CSCs and tumor propagation. CONCLUSION: We identified that XOR may represent a potential therapeutic target for clinical intervention in HCC driven by liver CSCs.
Authors: Madeline Niederkorn; Chiharu Ishikawa; Kathleen M Hueneman; James Bartram; Emily Stepanchick; Joshua R Bennett; Ashley E Culver-Cochran; Lyndsey C Bolanos; Emma Uible; Kwangmin Choi; Mark Wunderlich; John P Perentesis; Timothy M Chlon; Marie-Dominique Filippi; Daniel T Starczynowski Journal: Leukemia Date: 2021-08-31 Impact factor: 11.528