Wang Xiaofei, Wang Zehua, Li Sihan, Pattarayan Dhamotharan, Wang Yifei, Zhai Jingchen, Zhang Yu, Wang Haolin, Xu Meishu, Zhu Junjie, Wang Junmei, Ma Xiaochao, Mani Sridhar, Xie Wen, Zhang Min, Yang Da
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Struct Mol Biol. 2025 Aug 12. doi: 10.1038/s41594-025-01614-5.
Pregnane X receptor (PXR) is a nuclear receptor considered to be a master transcription factor of xenobiotic metabolism. Here, using enhanced ultraviolet crosslinking and immunoprecipitation, we show that PXR can bind mRNAs in different cancer cell lines and normal liver tissues. PXR-bound mRNAs include genes related to metabolic reprogramming and lipid metabolism. Separately from its known nuclear transcriptional function, cytoplasmic PXR binds and stabilizes mature mRNA containing C+G-enriched sequences through its zinc-finger domain. Mechanistically, cytoplasmic PXR interacts with RNH1, an RNase inhibitor, to regulate RNA stability. In colorectal cancer cells, cytoplasmic PXR facilitates glucose uptake by stabilizing SLC2A1 mRNA. This process further promotes cell proliferation and cancer development. Our study unveils a previously unknown dimension of PXR-mediated gene regulation by characterizing PXR as an RNA-binding protein important for mRNA stability in the cytoplasm.
孕烷X受体（PXR）是一种核受体，被认为是外源性物质代谢的主要转录因子。在此，我们通过增强紫外线交联和免疫沉淀表明，PXR可以在不同癌细胞系和正常肝组织中与mRNA结合。与PXR结合的mRNA包括与代谢重编程和脂质代谢相关的基因。与其已知的核转录功能不同，细胞质中的PXR通过其锌指结构域结合并稳定含有富含C+G序列的成熟mRNA。从机制上讲，细胞质中的PXR与核糖核酸酶抑制剂RNH1相互作用以调节RNA稳定性。在结肠癌细胞中，细胞质中的PXR通过稳定SLC2A1 mRNA促进葡萄糖摄取。这一过程进一步促进细胞增殖和癌症发展。我们的研究通过将PXR表征为一种对细胞质中mRNA稳定性很重要的RNA结合蛋白，揭示了PXR介导的基因调控一个以前未知的层面。
