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Cancer Lett. 2019 Dec 1;466:39-48. doi: 10.1016/j.canlet.2019.09.010. Epub 2019 Sep 20.

NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis.

Author information

1
Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Department of Pathophysiology, Dalian Medical University, Dalian, 116085, China; Department of Pathology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, China.
2
Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
3
Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: jymeiwh@shsmu.edu.cn.
4
Department of Pathophysiology, Dalian Medical University, Dalian, 116085, China. Electronic address: xr_blsl@dlmedu.edu.cn.
5
Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: rongcai@shsmu.edu.cn.

Abstract

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.

KEYWORDS:

Hepatocellular carcinoma; Nuclear factor erythroid-2 related factor 2; Reactive oxygen species; Serine synthesis; Small ubiquitin-like protein

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