Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Tianhe District, Guangzhou, Guangdong 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong, 510642, PR China.
Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Tianhe District, Guangzhou, Guangdong 510642, PR China; Key Laboratory of Zoonosis of Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou, Guangdong, 510642, PR China.
Toxicol Lett. 2019 Oct 15;315:77-86. doi: 10.1016/j.toxlet.2019.08.021. Epub 2019 Aug 27.
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.
T-2 毒素是农作物和饲料中的主要污染物。由于其在各种生物体中的高毒性，T-2 毒素作为对人类和动物养殖的威胁而备受关注。CYP1A1 的过度表达可能有助于致癌作用，CYP1A1 可能是预防和治疗人类恶性肿瘤的有希望的靶点。因此，了解 T-2 毒素诱导人细胞中 CYP1A1 表达的调控机制至关重要。在这项研究中，我们证实 T-2 毒素（100ng/ml）通过与启动子结合的 NRF1 和 Sp1 而不是通过众所周知的芳烃受体（AhR）诱导 HepG2 细胞中 CYP1A1 的表达。用 T-2 毒素处理的细胞中，Sp1 而非 NRF1 明显上调。然而，正如 IP 分析所示，T-2 毒素显然促进了 NRF1 和 Sp1 蛋白之间的相互作用。此外，在 T-2 毒素处理的 HepG2 细胞中，NRF1 的核转位增强，而 Sp1 的敲低则消除了 NRF1 的核富集。我们的结果表明，T-2 毒素在 HepG2 细胞中上调 CYP1A1 依赖于 Sp1 和 NRF1 之间相互作用的增强。这一发现表明 T-2 毒素的致癌特征可能与 CYP1A1 有关，这为理解 T-2 毒素的毒理学效应提供了新的见解。
