T-2 toxin upregulates the expression of human cytochrome P450 1A1 (CYP1A1) by enhancing NRF1 and Sp1 interaction. (15th October 2019)

• Record Type: Journal Article
• Authors: Ye, Wenchu; Lin, Ruqin; Chen, Xiaoxuan; Chen, Jiongjie; Chen, Ruohong; Xie, Xuan; Deng, Yiqun; Wen, Jikai
• Is Part Of: Toxicology letters. Volume 315(2019)
• Page Start: 77
• Page End: 86
• Publication Date: 2019-10-15
• Subjects: ActD Actinomycin D -- AhR Aromatic hydrocarbon receptors -- CYP1A1 Cytochrome P450 1A1 -- ChIP Chromatin immunoprecipitation assay -- DAPA DNA affinity precipitation assay -- HepG2 Human hepatocellular carcinoma cells -- IF Immunofluorescent -- IP Immunoprecipitation -- NRF1 Nuclear respiratory factor 1 -- ORF Open reading frame -- Sp1 Specificity Protein 1 -- WT Wild type; T-2 toxin -- CYP1A1 -- NRF1 -- Sp1 -- Molecular mechanism; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.08.021
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: T-2 toxin could promote NRF1 translocation from the cytoplasm to the nucleus and facilitate the cooperative protein-protein interaction between NRF1 and Sp1, then upregulated the CYP1A1 expression. Highlights: NRF1 and Sp1 jointly regulated the T-2 toxin-induced expression of CYP1A1 . T-2 toxin promoted the interaction between NRF1 and Sp1. Sp1 is required for nuclear translocation of NRF1 in response to T-2 toxin. NRF1 is a novel regulator of CYP1A1. Abstract: T-2 toxin is a major pollutant in crops and feedstuffs. Due to its high toxicity in a variety of organisms, T-2 toxin is of great concern as a threat to humans and to animal breeding. Overexpression of CYP1A1 may contribute to carcinogenesis, and CYP1A1 may be a promising target for the prevention and treatment of human malignancies. Therefore, it is essential to understand the regulatory mechanism by which T-2 toxin induces CYP1A1 expression in human cells. In this study, we confirmed that T-2 toxin (100 ng/mL) induced the expression of CYP1A1 in HepG2 cells through NRF1 and Sp1 bound to the promoter instead of through the well-recognized Aromatic hydrocarbon receptors (AhR). In cells treated with T-2 toxin, Sp1, but not NRF1, was significantly upregulated. However, T-2 toxin apparently promoted the interaction between NRF1 and Sp1 proteins, as revealed by IP analysis. Furthermore, in T-2 toxin-treated HepG2 cells, nuclear translocation of NRF1 was enhanced, while knockdown of Sp1 ablated NRF1 nuclear enrichment. Our results revealed that the upregulation of CYP1A1 by T-2 toxin in HepG2 cells depended on enhanced interaction between Sp1 and NRF1. This finding suggests the tumorigenic features of T-2 toxin might be related to the CYP1A1, which provides new insights to understand the toxicological effect of T-2 toxin.