Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression. (21st March 2020)

• Record Type: Journal Article
• Authors: Qi, Jie; Chen, Xiangyuan; Wu, Qichao; Wang, Jing; Zhang, Hao; Mao, Anrong; Zhu, Minmin; Miao, Changhong
• Other Names: Wahab Rizwan Guest Editor.
• Is Part Of: Oxidative medicine and cellular longevity. Volume 2020(2020)
• Publication Date: 2020-03-21
• Subjects: Oxidative stress -- Periodicals; Cells -- Aging -- Periodicals; Cells -- Aging; Oxidative stress; Oxidative Stress -- Periodicals; Cell Aging -- Periodicals; Periodicals; 611.0181
• DOI: 10.1155/2020/3985089
• Languages: English
• ISSNs: 1942-0900

Abstract

Abstract : Background . Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. Methods . We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1 α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1 α interacts with SET8. In vivo experiments were performed to verify the conclusions from the in vitro experiments. Results . Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro and in vivo results demonstrated that fasting decreased cell viability and downregulated expression of SET8, Nrf2, and downstream effectors of Nrf2, while it upregulated Keap1 expression, mediated ROS accumulation, and induced HCC cell apoptosis. These results were similar to what is observed in SET8-deficient cells. Furthermore, SET8 was found to interact with PGC1 α, and both PGC1 α and H4K20me1, a downstream target of SET8, were found to be enriched at the Keap1 promoter region. These two factors were further determined to attenuate Keap1 promoter activity. Conclusions . The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1 α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.