NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis

• Published in: Cancer letters 2019-12, Vol.466, p.39-48
• Main Authors: Guo, Haoyan, Xu, Jiaqian, Zheng, Quan, He, Jianli, Zhou, Wei, Wang, Kezhou, Huang, Xian, Fan, Qiuju, Ma, Jiao, Cheng, Jinke, Mei, Wenhan, Xing, Rong, Cai, Rong
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Biosynthesis; Cancer; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Line, Tumor; Enzymes; Experiments; Female; Hep G2 Cells; Hepatocellular carcinoma; Homeostasis; Humans; Kinases; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lysine; Metabolism; Mice; Mutation; Neoplasm Transplantation; NF-E2-Related Factor 2 - chemistry; NF-E2-Related Factor 2 - metabolism; Nuclear factor erythroid-2 related factor 2; Oxidative Stress; Penicillin; Phenotypes; Phosphoglycerate dehydrogenase; Phosphoglycerate Dehydrogenase - metabolism; Phosphorylation; Plasmids; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Serine; Serine - metabolism; Serine synthesis; Signal transduction; Small ubiquitin-like protein; Stress, Physiological; SUMO protein; Sumoylation; Transcription factors; Tumorigenesis
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.09.010

Nuclear factor erythroid-2 related factor 2 (NRF2) is a pivotal transcription factor that maintains cellular redox homeostasis and facilitates the development of malignant tumor phenotypes. At the molecular level, NRF2 promotes de novo serine synthesis and SUMOylation affects its function. Our results indicated that the SUMO1 acceptor site of NRF2 is the conserved lysine residue 110 (K110), and that NRF2 SUMOylation deficiency inhibited tumorigenesis in hepatocellular carcinoma (HCC). Mechanistically, NRF2 SUMOylation promoted de novo serine synthesis in HCC by enhancing the clearance of intracellular reactive oxygen species (ROS) and up-regulating phosphoglycerate dehydrogenase (PHGDH). More importantly, serine starvation increased the level of NRF2 SUMOylation, leading to sustained HCC growth. Collectively, our results indicate the presence of a novel NRF2 SUMOylation-mediated signaling process that maintains HCC tumorigenesis in normal conditions and in response to metabolic stress. •NRF2 is conjugated by SUMO1 at K110.•NRF2 SUMOylation maintains HCC tumorigenesis.•NRF2 SUMOylation promotes de novo serine synthesis in HCC via ROS-PHGDH signaling.•Serine starvation induces NRF2 SUMOylation.