Gankyrin has an antioxidative role through the feedback regulation of Nrf2 in hepatocellular carcinoma.
Oxidative stress status has a key role in hepatocellular carcinoma (HCC) development and progression. Normally, reactive oxygen species (ROS) levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors. How HCC cells respond to excessive oxidative stress remains elusive. Here, we identified a feedback loop between gankyrin, an oncoprotein overexpressed in human HCC, and Nrf2 maintaining the homeostasis in HCC cells. Mechanistically, gankyrin was found to interact with the Kelch domain of Keap1 and effectively competed with Nrf2 for Keap1 binding. Increased expression of gankyrin in HCC cells blocked the binding between Nrf2 and Keap1, inhibiting the degradation of Nrf2 by proteasome. Interestingly, accumulation and translocation of Nrf2 increased the transcription of gankyrin through binding to the ARE elements in the promoter of gankyrin. The positive feedback regulation involving gankyrin and Nrf2 modulates a series of antioxidant enzymes, thereby lowering intracellular ROS and conferring a steadier intracellular environment, which prevents mitochondrial damage and cell death induced by excessive oxidative stress. Our results indicate that gankyrin is a regulator of cellular redox homeostasis and provide a link between oxidative stress and the development of HCC.
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Chun
C
Yang
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Ye-Xiong
YX
Tan
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China.
Guang-Zhen
GZ
Yang
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Jian
J
Zhang
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Yu-Fei
YF
Pan
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Chen
C
Liu
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Jing
J
Fu
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Yao
Y
Chen
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China.
Zhi-Wen
ZW
Ding
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China hywangk@vip.sina.com donliwei@126.com.
Li-Wei
LW
Dong
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, 200433 Shanghai, China National Center for Liver Cancer, 200032 Shanghai, China State Key Laboratory of Oncogenes and related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200240 Shanghai, China hywangk@vip.sina.com donliwei@126.com.
Hong-Yang
HY
Wang
D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000276:immunology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology*; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology*; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology; D020218:Response Elements / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D046988:Proteasome Endopeptidase Complex